Androgen receptor modulators and methods of use thereof

ABSTRACT

Compounds of structural formula (I) are disclosed as useful for modulating the androgen receptor (AR) in a tissue selective manner in a patient in need of such modulation, and in particular for antagonizing AR in the prostate of a male patient or in the uterus of a female patient and agonizing AR in bone and/or muscle tissue. These compounds are useful in the treating conditions caused by androgen deficiency or which can be ameliorated by androgen administration, including: osteoporosis, periodontal disease, bone fracture, bone damage following bone reconstructive surgery, sarcopenia, frailty, aging skin, male hypogonadism, female sexual dysfunction, post-menopausal symptoms in women, atherosclerosis, hypercholesterolemia, hyperlipidemia, aplastic anemia and other hematopoietic disorders, pancreatic cancer, renal cancer, prostate cancer, arthritis and joint repair, alone or in combination with other active agents. In addition, these compounds are useful as pharmaceutical composition ingredients alone and in combination with other active agents.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a national stage entry under 35 U.S.C. § 371 ofPCT/US02/33232, filed Oct. 15, 2002, which claims the benefit of U.S.Provisional Application No. 60/334,866 filed Oct. 19, 2001.

BACKGROUND OF THE INVENTION

Androgens play important roles in post-natal development that are mostpronounced at adrenarche and pubarche. Androgen production promotes themusculoskeletal anabolism associated with the pubertal growth in bothmales and females. At puberty, ovarian and testicular androgens areresponsible for pubertal hair, acne, and enhancement of libido. Inmales, exposure to 100-fold increased levels of endogenous androgensresults in the gender dimorphism in bone mass, muscle mass (positivenitrogen balance), and upper body strength, and are required for normalsexual development (genitalia, spermatogenesis, prostate and seminalvesicle maturation). Delay in puberty decreases the peak bone massachieved during adulthood. (Bhasin, S., et al., Eds. Pharmacology,Biology, and Clinical Applications of Androgens: Current Status andFuture Prospects. Wiley-Liss, Inc.: New York, 1996). In women, naturalmenopause causes virtually complete loss of ovarian estrogen productionand gradually reduces ovarian production of androgen by approximately50%. The physiological consequences of reduced androgen production aftermenopause are evident in decreased energy and libido, and contributesignificantly in many women to vasomotor symptoms. Decreased androgenoutput is also thought to contribute—along with declining pituitarygrowth hormone (GH) secretion and insulin derived growth factor 1 (IGF1)action—to age-dependent sarcopenia, negative nitrogen balance and lossof bone mass. (Vestergaard, et al., Effect of sex hormone replacement onthe insulin-like growth factor system and bone mineral: across-sectional and longitudinal study in 595 perimenopausal womenparticipating in the Danish Osteoporosis Prevention Study, J ClinEndocrinol Metab. 84:2286–90, 1999; and Bhasin, et al., Eds.Pharmacology, Biology, and Clinical Applications of Androgens: CurrentStatus and Future Prospects, Wiley-Liss, Inc.: New York. 1996).Postmenopausal osteoporosis results mainly from estrogen deficiency.However, many women who received estrogen replacement therapy still losebone with age and develop age-related osteoporotic fractures (albeit ata lower rate than those taking estrogens), indicating that bothestrogens and androgens play important roles for bone health in bothwomen and men. The simultaneous decreases in bone mass, muscle mass andmuscle strength increase the risk of falls and especially of hipfractures in both men and women >65 years of age. In fact, one-third ofall hip fractures occur in men.

The androgen receptor (AR) belongs to the nuclear receptor superfamilyand controls transcription in a ligand dependent manner (Brinkman, etal., Mechanisms of androgen receptor activation and function, J. Ster.Biochem. Mol. Biol. 69, 307–313, 1999). Upon androgen binding, AR bindsdirectly to specific DNA sequences present in the promoter region ofandrogen responsive genes, termed androgen response elements (AREs), tostimulate transcription. Ligands that interact witht the AR and activateor repress gene transcription are classified as AR agonists, whereasligands that interact with AR and block transactivation ortransrepression of genes induced by endogenous androgens are classifiedas AR antagonists. A number of natural or synthetic androgen agonistshave been used for treatment of musculoskeletal or hematopoieticdisorders and for hormone replacement therapy. In addition, ARantagonists, such as flutamide or bicalutamide, are used for treatmentof prostate cancer. However, clinical use of these androgen agonists orantagonists have been limited because of undesirable effects, such ashirsutism and prostate enlargement for agonists, and bone loss,fracture, gynecomastia and sarcopenia for antagonists. It would beuseful to have available androgens with tissue selective agonisticactivity, which increase bone formation and muscle mass but do notinduce the virilization.

Osteoporosis is characterized by bone loss, resulting from an imbalancebetween bone resorption (destruction) and bone formation, which startsin the fourth decade continues throughout life at the rate of about 1–4%per year (Eastell, Treatment of postmenopausal osteoporosis, New Eng. J.Med. 338: 736, 1998). In the United States, there are currently about 20million people with detectable fractures of the vertebrae due toosteoporosis. In addition, there are about 250,000 hip fractures peryear due to osteoporosis, associated with a 12%–20% mortality ratewithin the first two years, while 30% of patients require nursing homecare after the fracture and many never become fully ambulatory again. Inpostmenopausal women, estrogen deficiency leads to increased boneresorption resulting in bone loss in the vertebrae of around 5% peryear, immediately following menopause. Thus, first linetreatment/prevention of this condition is inhibition of bone resorptionby bisphosphonates, estrogens, selective estrogen receptor modulators(SERMs) and calcitonin. However, inhibitors of bone resorption are notsufficient to restore bone mass for patients who have already lost asignificant amount of bone. The increase in spinal BMD attained bybisphosphonate treatment can reach 11% after 7 years of treatment withalendronate. In addition, as the rate of bone turnover differs from siteto site; higher in the trabecular bone of the vertebrae than in thecortex of the long bones, the bone resorption inhibitors are lesseffective in increasing hip BMD and preventing hip fracture. Therefore,osteoanabolic agents, which increase cortical/periosteal bone formationand bone mass of long bones, would address an unmet need in thetreatment of osteoporosis especially for patients with high risk of hipfractures. The osteoanabolic agents also complement the bone resorptioninhibitors that target the trabecular envelope, leading to abiomechanically favorable bone structure. (Schmidt, et al., Anabolicsteroid: Steroid effects on bone in women, 1996, In: J. P. Bilezikian,et al., Ed. Principles of Bone Biology. San Diego: Academic Press.)

A number of studies provide the proof of principle that androgens areosteoanabolic in women and men. Anabolic steroids, such as nandrolonedecanoate or stanozolol, have been shown to increase bone mass inpostmenopausal women. Beneficial effects of androgens on bone inpost-menopausal osteoporosis are well-documented in recent studies usingcombined testosterone and estrogen administration (Hofbauer, et al.,Androgen effects on bone metabolism: recent progress and controversies,Eur. J. Endocrinol. 140, 271–286, 1999). Combined treatment increasedsignificantly the rate and extent of the rise in BMD (lumbar and hip),relative to treatment with estrogen alone. Additionally,estrogen—progestin combinations that incorporate an androgenic progestin(norethindrone) rather than medroxyprogesterone acetate yielded greaterimprovements in hip BMD. These results have recently been confirmed in alarger (N=311) 2 year, double blind comparison study in which oralconjugated estrogen (CEE) and methyltestosterone combinations weredemonstrated to be effective in promoting accrual of bone mass in thespine and hip, while conjugated estrogen therapy alone prevented boneloss (A two-year, double-blind comparison of estrogen-androgen andconjugated estrogens in surgically menopausal women: Effects on bonemineral density, symptoms and lipid profiles. J Reprod Med.44(12):1012–20, 1999). Despite the beneficial effects of androgens inpostmenopausal women, the use of androgens has been limited because ofthe undesirable virilizing and metabolic action of androgens. The datafrom Watts and colleagues demonstrate that hot flushes decrease in womentreated with CEE+methyltestosterone; however, 30% of these womensuffered from significant increases in acne and facial hair, acomplication of all current androgen pharmacotherapies (Watts, et al.,Comparison of oral estrogens and estrogens plus androgen on bone mineraldensity, menopausal symptoms, and lipid-lipoprotein profiles in surgicalmenopause, Obstet. Gynecol. 85, 529–537, 1995). Moreover, the additionof methyltestosterone to CEE markedly decreased HDL levels, as seen inother studies. Thus, the current virilizing and metabolic side effectprofile of androgen therapies provide a strong rationale for developingtissue selective androgen agonists for bone.

It is well established that androgens play an important role in bonemetabolism in men, which parallels the role of estrogens in women.(Anderson, et al., Androgen supplementation in eugonadal men withosteoporosis—effects of 6 months of treatment on bone mineral densityand cardiovascular risk factors, Bone 18: 171–177, 1996). Even ineugonadal men with established osteoporosis, the therapeutic response totestosterone treatment provides additional evidence that androgens exertimportant osteoanabolic effects. Mean lumbar BMD increased from 0.799gm/cm² to 0.839 g/cm², in 5 to 6 months in response to 250 mg oftestosterone ester IM q fortnight (p=0.001). A common scenario forandrogen deficiency occurs in men with stage D prostate cancer(metastatic) who undergo androgen deprivation therapy (ADT). Endocrineorchiectomy is achieved by long acting GnRH agonists, while androgenreceptor blockade is implemented with flutamide or bicalutamide (ARantagonists). In response to hormonal deprivation, these men suffer fromhot flushes, significant bone loss, weakness, and fatigue. In a recentpilot study of men with stage D prostate cancer, osteopenia (50% vs.38%) and osteoporosis (38% vs. 25%) were more common in men who hadundergone ADT for >1 yr than the patients who did not undergo ADT (Wei,et al. Androgen deprivation therapy for prostate cancer results insignificant loss of bone density, Urology 54: 607–11, 1999). Lumbarspine BMD was significantly lower in men who had undergone ADT(P=0.008). Thus, in addition to the use of tissue selective AR agonistsfor osteoporosis, tissue selective AR antagonists in the prostate thatlack antagonistic action in bone and muscle may be a useful treatmentfor prostate cancer, either alone or as an adjunct to traditional ADTsuch as GnRH agonist/antagonist. (See also Stoche, et al., J Clin.Endocrin. Metab. 86:2787–91, 2001).

Additionally, it has been reported that patients with pancreatic cancertreated with the antiandrogen flutamide have been found to haveincreased survival time. (Greenway, B. A., Drugs & Aging, 17(3), 161,2000). The tissue selective androgen receptor modulators of the presentinvention may be employed for treatment of pancreatic cancer, eitheralone or as an adjunct to treatment with an antiandrogen.

The possibility of tissue selective AR agonism was suggested by androgeninsensitivity syndrome (AIS), which results from mutations in AR genelocated at X chromosome. (Quigley, et al., Androgen receptor defects:Historical, clinical, and molecular perspectives. Endocrine Reviews.16:546–546, 1995). These mutations cause different degrees of androgeninsensitivity. While complete lack of androgen responsiveness developsas a female phenotype with female-type bones, subtle mutations (oneamino acid substitution) of AR may lead to partial AIS with differentdegrees of abnormality in male sexual development often with male-typeskeleton. A similar aberration in male sex organ development is alsofound in individuals with mutations in 5α-reductase type 2 gene, thatconverts testosterone to 5α-dihydro-testosterone (5α-DHT) (Mendonca, etal., Male pseudohermaphroditism due to steroid 5alpha-reductase 2deficiency: Diagnosis, psychological evaluation, and management,Medicine (Baltimore), 75:64–76 (1996)). These patients exhibit partialdevelopment of male organs with normal male skeleton, indicating thattestosterone cannot substitute for 5α-DHT as an activator of AR ingenital development. This ligand specificity for certain tissues raisesthe possibility that androgenic compounds with AR agonistic activitycould have specificity for certain tissues, such as bone, while lackingactivity in other tissues, such as those responsible for virilization.

Recent advances in the steroid hormone receptor field uncovered thecomplex nature of transcription controlled by AR and other nuclearreceptors (Brinkman, et al., Mechanisms of androgen receptor activationand function, J. Ster. Biochem. Mol. Biol. 69:307–313 1999). Uponbinding to ARE as a homo-dimer, agonist-bound AR stimulatestranscription by recruiting a large enzymatic co-activator complex thatincludes GRIP1/TIF2, CBP/p300 and other coactivators. Transcriptionalactivities of AR have been functionally mapped to both the N-terminaldomain (NTD) and C-terminal ligand binding domain (LBD), also termedactivation function AF1 and AF2, respectively. A feature of AR is theligand mediated interaction of AR NTD with LBD (N-C interaction) whichis essential for most ligand induced transcriptional activation. Inaddition, agonist-bound AR can also suppress transcription viaprotein-protein interaction with transcription factor complexes such asAP1, NFκB and Ets family. Both AR agonist-induced transcriptionalactivation and repression are context (cell type and promoter) dependentand are reversed by AR antagonists, providing the possibility forligand-dependent, context specific agonism/antagonism. Androgenicligands, thus, may lead to tissue selective AR agonism or partial ARagonism/antagonism, and have been named selective AR modulators (SARMs).

What is needed in the art are compounds that can produce the samepositive responses as androgen replacement therapy without the undesiredside effects. Also needed are androgenic compounds that exert selectiveeffects on different tissues of the body. In this invention, wedeveloped a method to identify SARMs using a series of in vitrocell-assays that profiles ligand mediated activation of AR, such as (i)N-C interaction, (ii) transcriptional repression, (iii) transcriptionalactivation dependent on AF1 or AF2 or native form of AR. SARM compoundsin this invention, identified with the methods listed above, exhibittissue selective AR agonism in vivo, i.e. agonism in bone (stimulationof bone formation in rodent model of osteoporosis) and antagonism inprostate (minimal effects on prostate growth in castrated rodents andantagonism of prostate growth induced by AR agonists). Such compoundsare ideal for treatment of osteoporosis in women and men as amonotherapy or in combination with inhibitors of bone resorption, suchas bisphosphonates, estrogens, SERMs, cathepsin K inhibitors, αVβ3antagonists, calcitonin, proton pump inhibitors. SARM compounds may alsobe employed for treatment of prostate disease, such as prostate cancerand benign prostate hyperplasia (BPH). Moreover, compounds in thisinvention exhibit minimal effects on skin (acne and facial hair growth)and can be used for treatment of hirsutism. Additionally, compounds inthis invention can exhibit muscle growth and can be used for treatmentof sarcopenia and frailty. Moreover, compounds in this invention canexhibit androgen agonism in the central nervous system and can be usedto treat vasomotor symptoms (hot flush) and can increase energy andlibido, particularly in post-menopausal women. The compounds of thepresent invention may also be used in particular to treat female sexualdysfunction. The compounds of the present invention may be used in thetreatment of prostate cancer, either alone or as an adjunct totraditional GnRH agonist/antagonist therapy for their ability to restorebone, or as a replacement for antiandrogen therapy because of theability to antagonize androgen in the prostate, and minimize bonedepletion in the skeletal system. Further, the compounds of the presentinvention may be used for their ability to restore bone in the treatmentof pancreatic cancer as an adjunct to treatment with antiandrogen, or assolo agents for their antiandrogenic properties, offering the advantageover traditional antiandrogens of being bone-sparing. Additionally,compounds in this invention can increase the number of blood cells, suchas red blood cells and platelets and can be used for treatment ofhematopoietic disorders such as aplastic anemia. Finally, compounds inthis invention have minimal effects on lipid metabolism, thusconsidering their tissue selective androgen agonism listed above, thecompounds in this invention are ideal for hormone replacement therapy inhypogonadic (androgen deficient) men.

EP 1 002 799 assigned to Pfizer describes an optically pure androgenmediator of structural formula:

for use in the prevention and restoration of age-related decline inmuscle mass and strength and the treatment of conditions which presentwith low bone mass in mammals, including humans.

U.S. Pat. No. 6,017,924, assigned to Ligand Pharmaceuticals, Inc.,claims a compound of structural formula:

and its use as an androgen receptor modulator.

U.S. Pat. No. 5,688,808, assigned to Ligand Pharmaceuticals, Inc.,claims compounds of structural formula:

as steroid receptor modulator compounds.

U.S. Pat. No. 5,696,130, assigned to Ligand Pharmaceuticals, Inc.,claims compounds of structural formulae:

as high affinity, high selectivity modulators for steroid receptors.U.S. Pat. No. 6,093,821 is a divisional of U.S. Pat. No. 5,696,130, andclaims a method for producing 6-substituted-1,2-dihydro N-1 protectedquinolines.

PCT publication WO 01/16133, assigned to Ligand Pharmaceuticals, Inc.,describes 8-substituted-6-trifluoromethyl-9-pyrido[3,2,-g]quinolinecompounds of structural formulae:

as androgen receptor modulators.

PCT publication WO 01/16139 assigned to Ligand Pharmaceuticals, Inc.,describes compounds of structural formulae:

as agonists, partial agonists and antagonists for the androgen receptor.

SUMMARY OF THE INVENTION

Compounds of structural formula (I):

and pharmaceutically acceptable salts thereof are useful in modulatingthe androgen receptor in a tissue selective manner in a patient in needof such modulation, as well as in a method of agonizing the androgenreceptor in a patient, and in particular the method wherein the androgenreceptor is agonized in bone and/or muscle tissue and antagonized in theprostate of a male patient or in the uterus of a female patient. Thesecompounds are useful in the treatment of conditions caused by androgendeficiency or which can be ameliorated by androgen administration,including: osteoporosis, periodontal disease, bone fracture, bone damagefollowing bone reconstructive surgery, sarcopenia, frailty, aging skin,male hypogonadism, female sexual dysfunction, post-menopausal symptomsin women, atherosclerosis, hypercholesterolemia, hyperlipidemia,aplastic anemia and other hematopoietic disorders, pancreatic cancer,renal cancer, prostate cancer, arthritis and joint repair, alone or incombination with other active agents. In particular, the compounds ofthe present invention are useful in treating glucocorticoid-inducedosteoporosis. In addition, these compounds are useful as pharmaceuticalcomposition ingredients alone and in combination with other activeagents.

The invention is also concerned with novel compounds of structuralformula I, and pharmaceutically acceptable salts thereof.

The invention is also concerned with pharmaceutical formulationscomprising one of the compounds as an active ingredient.

The invention is further concerned with processes for preparing thecompounds of this invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds of structural formula (I):

wherein:

-   X is selected from —O—, and —N(R⁴)—;-   R¹ is selected from hydrogen, C₁₋₃ alkyl, cyclopropyl and    trifluoromethyl;-   R² is selected from:    -   (1) hydrogen,    -   (2) C₁₋₈ alkyl,    -   (3) C₃₋₈ cycloalkyl,    -   (4) C₃₋₈ cycloheteroalkyl,    -   (5) C₃₋₈ cycloalkyl-C₁₋₆ alkyl,    -   (6) C₃₋₈ cycloheteroalkyl-C₁₋₆ alkyl,    -   (7) aryl,    -   (8) aryl-C₁₋₆ alkyl,    -   (9) amino,    -   (10) amino-C₁₋₆ alkyl,    -   (11) C₁₋₃ acylamino,    -   (12) C₁₋₃ acylamino-C₁₋₆ alkyl,    -   (13) (C₁₋₆ alkyl)_(n) amino,    -   (14) C₃₋₆ cycloalkyl-C₀₋₂ alkylamino,    -   (15) (C₁₋₆ alkyl)_(n) amino-C₁₋₆ alkyl,    -   (16) C₁₋₆ alkoxy,    -   (17) C₁₋₄ alkoxy-C₁₋₆ alkyl,    -   (18) hydroxycarbonyl,    -   (19) hydroxycarbonyl-C₁₋₆ alkyl,    -   (20) C₁₋₃ alkoxycarbonyl,    -   (21) C₁₋₃ alkoxycarbonyl-C₁₋₆ alkyl,    -   (22) hydroxy,    -   (23) hydroxy-C₁₋₆ alkyl,    -   (24) nitro,    -   (25) cyano,    -   (26) trifluoromethyl,    -   (27) trifluoromethoxy,    -   (28) trifluoroethoxy,    -   (29) C₁₋₈ alkyl-S(O)_(p)—,    -   (30) (C₁₋₈ alkyl)_(p)aminocarbonyl,    -   (31) C₁₋₈ alkyloxycarbonylamino,    -   (32) (C₁₋₈ alkyl)_(n) aminocarbonyloxy,    -   (33) (aryl C₁₋₃ alkyl)_(n) amino,    -   (34) (aryl)_(n) amino,    -   (35) aryl-C₁₋₃ alkylsulfonylamino, and    -   (36) C₁₋₈ alkylsulfonylamino;-   R³ is selected from hydrogen, C₁₋₈ alkyl, and trifluoromethyl;-   or R² and R³ together with the carbon atom to which they are    attached form a carbonyl group, or join to form a 3- to 6-membered    spiro-carbocyclic ring; and wherein the alkyl groups in R² and R³    are either unsubstituted or substituted with one to three R⁵    substituents and wherein any of the aryl, cycloalkyl, or    cycloheteroalkyl groups in R² are either unsubstituted or    substituted with one to three R⁶ substituents;-   R⁴ is selected from:    -   (1) hydrogen,    -   (2) aryl,    -   (3) aminocarbonyl,    -   (4) C₃₋₈ cycloalkyl,    -   (5) amino C₁₋₆ alkyl,    -   (6) (aryl)_(p)aminocarbonyl,    -   (7) (aryl C₁₋₅ alkyl)_(p)aminocarbonyl,    -   (8) hydroxycarbonyl C₁₋₆ alkyl,    -   (9) C₁₋₈ alkyl,    -   (10) perfluoro C₁₋₈ alkyl,    -   (11) aryl C₁₋₆ alkyl,    -   (12) (C₁₋₆ alkyl)_(p)amino C₂₋₆ alkyl,    -   (13) (aryl C₁₋₆ alkyl)_(p)amino C₂₋₆ alkyl,    -   (14) C₁₋₈ alkylsulfonyl,    -   (15) C₁₋₈ alkoxycarbonyl,    -   (16) aryloxycarbonyl,    -   (17) aryl C₁₋₈ alkoxycarbonyl,    -   (18) C₁₋₈ alkylcarbonyl,    -   (19) arylcarbonyl,    -   (20) aryl C₁₋₆ alkylcarbonyl,    -   (21) (C₁₋₈ alkyl)_(p)aminocarbonyl,    -   (22) aminosulfonyl,    -   (23) C₁₋₈ alkylaminosulfonyl,    -   (24) (aryl)_(p)aminosulfonyl,    -   (25) (aryl C₁₋₈ alkyl)_(p)aminosulfonyl,    -   (26) arylsulfonyl,    -   (27) aryl C₁₋₆ alkylsulfonyl,    -   (28) C₁₋₆ alkylthiocarbonyl,    -   (29) arylthiocarbonyl, and    -   (30) aryl C₁₋₆ alkylthiocarbonyl,-   wherein any of the alkyl groups of R⁴ are either unsubstituted or    substituted with one to three R⁵ substituents and wherein any of the    aryl, cycloalkyl, or cycloheteroalkyl groups in R⁴ are either    unsubtituted or substituted with one to three R⁶ substituents;-   each R⁵ is independently selected from:    -   (1) halogen,    -   (2) C₁₋₈ alkyl,    -   (3) C₃₋₈ cycloalkyl,    -   (4) C₃₋₈ cycloheteroalkyl,    -   (5) C₃₋₈ cycloalkyl-C₁₋₆ alkyl,    -   (6) C₃₋₈ cycloheteroalkyl-C₁₋₆ alkyl,    -   (7) aryl,    -   (8) aryl-C₁₋₆ alkyl,    -   (9) amino,    -   (10) amino-C₁₋₆ alkyl,    -   (11) C₁₋₃ acylamino,    -   (12) C₁₋₃ acylamino-C₁₋₆ alkyl,    -   (13) (C₁₋₆ alkyl)_(n) amino,    -   (14) C₃₋₆ cycloalkyl-C₀₋₂ alkylamino,    -   (15) (C₁₋₆ alkyl)_(n) amino-C₁₋₆ alkyl,    -   (16) C₁₋₆ alkoxy,    -   (17) C₁₋₄ alkoxy-C₁₋₆ alkyl,    -   (18) hydroxycarbonyl,    -   (19) hydroxycarbonyl-C₁₋₆ alkyl,    -   (20) C₁₋₃ alkoxycarbonyl,    -   (21) C₁₋₃ alkoxycarbonyl-C₁₋₆ alkyl,    -   (22) hydroxy,    -   (23) hydroxy-C₁₋₆ alkyl,    -   (24) nitro,    -   (25) cyano,    -   (26) trifluoromethyl,    -   (27) trifluoromethoxy,    -   (28) trifluoroethoxy,    -   (29) C₁₋₈ alkyl-S(O)_(p)—,    -   (30) (C₁₋₈ alkyl)_(p)aminocarbonyl,    -   (31) C₁₋₈ alkyloxycarbonylamino,    -   (32) (C₁₋₈ alkyl)_(n) aminocarbonyloxy,    -   (33) (aryl C₁₋₃ alkyl)_(n) amino,    -   (34) (aryl)_(n) amino,    -   (35) aryl-C₁₋₃ alkylsulfonylamino, and    -   (36) C₁₋₈ alkylsulfonylamino;-   each R⁶ is independently selected from:    -   (1) halogen,    -   (2) aryl,    -   (3) C₁₋₈ alkyl,    -   (4) C₃₋₈ cycloalkyl,    -   (5) C₃₋₈ cycloheteroalkyl,    -   (6) aryl C₁₋₆alkyl,    -   (7) amino C₀₋₆alkyl,    -   (8) C₁₋₆ alkylamino C₀₋₆alkyl,    -   (9) (C₁₋₆ alkyl)₂amino C₀₋₆alkyl,    -   (10) aryl C₀₋₆ alkylamino C₀₋₆alkyl,    -   (11) (aryl C₀₋₆ alkyl)₂amino C₀₋₆alkyl,    -   (12) C₁₋₆ alkylthio,    -   (13) aryl C₀₋₆alkylthio,    -   (14) C₁₋₆ alkylsulfinyl,    -   (15) aryl C₀₋₆alkylsulfinyl,    -   (16) C₁₋₆ alkylsulfonyl,    -   (17) aryl C₀₋₆alkylsulfonyl,    -   (18) C₁₋₆ alkoxy C₀₋₆alkyl,    -   (19) aryl C₀₋₆ alkoxy C₀₋₆alkyl,    -   (20) hydroxycarbonyl C₀₋₆alkyl,    -   (21) C₁₋₆ alkoxycarbonyl C₀₋₆alkyl,    -   (22) aryl C₀₋₆ alkoxycarbonyl C₀₋₆alkyl,    -   (23) hydroxycarbonyl C₁₋₆ alkyloxy,    -   (24) hydroxy C₀₋₆alkyl,    -   (25) cyano,    -   (26) nitro,    -   (27) perfluoroC₁₋₄alkyl,    -   (28) perfluoroC₁₋₄alkoxy,    -   (29) oxo,    -   (30) C₁₋₆ alkylcarbonyloxy,    -   (31) aryl C₀₋₆alkylcarbonyloxy,    -   (32) alkyl C₁₋₆ carbonylamino,    -   (33) aryl C₀₋₆ alkylcarbonylamino,    -   (34) C₁₋₆ alkylsulfonylamino,    -   (35) aryl C₀₋₆alkylsulfonylamino,    -   (36) C₁₋₆ alkoxycarbonylamino,    -   (37) aryl C₀₋₆ alkoxycarbonylamino,    -   (38) C₁₋₆alkylaminocarbonylamino,    -   (39) aryl C₀₋₆alkylaminocarbonylamino,    -   (40) (C₁₋₆alkyl)₂ aminocarbonylamino,    -   (41) (aryl C₀₋₆alkyl)₂ aminocarbonylamino,    -   (42) (C₁₋₆alkyl)₂ aminocarbonyloxy,    -   (43) (aryl C₀₋₆alkyl)₂ aminocarbonyloxy,    -   (44) C₀₋₆alkylcarbonyl C₀₋₆alkyl, and    -   (45) aryl C₀₋₆alkylcarbonyl C₀₋₆alkyl;-   n is selected from 1 and 2;-   p is selected from 0, 1, and 2;-   and pharmaceutically acceptable salts thereof.

The term “alkyl” shall mean straight or branched chain alkanes of one toten total carbon atoms, or any number within this range (i.e., methyl,ethyl, 1-propyl, 2-propyl, n-butyl, s-butyl, t-butyl, etc.). The term“C₀ alkyl” (as in “C₀₋₈ alkylaryl”) shall refer to the absence of analkyl group.

The term “alkenyl” shall mean straight or branched chain alkenes of twoto ten total carbon atoms, or any number within this range.

The term “alkynyl” shall mean straight or branched chain alkynes of twoto ten total carbon atoms, or any number within this range.

The term “cycloalkyl” shall mean cyclic rings of alkanes of three toeight total carbon atoms, or any number within this range (i.e.,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl orcyclooctyl).

The term “cycloheteroalkyl,” as used herein, shall mean a 3- to8-membered fully saturated heterocyclic ring containing one or twoheteroatoms chosen from N, O, or S and optionally fused to another fullysaturated ring. Examples of cycloheteroalkyl groups include, but are notlimited to piperidinyl, pyrrolidinyl, azetidinyl, morpholinyl,piperazinyl, and octahydroquinolizinyl. In one embodiment of the presentinvention cycloheteroalkyl is selected from piperidinyl, pyrrolidinyl,and morpholinyl.

The term “alkoxy,” as used herein, refers to straight or branched chainalkoxides of the number of carbon atoms specified (e.g., C₁₋₅ alkoxy),or any number within this range (i.e., methoxy, ethoxy, etc.).

The term “aryl,” as used herein, refers to a monocyclic or bicyclicsystem comprising at least one aromatic ring, wherein the monocylic orbicyclic system contains 0, 1, 2, 3, or 4 heteroatoms chosen from N, O,or S, and wherein the monocylic or bicylic system is eitherunsubstituted or substituted with one or more groups independentlyselected from hydrogen, halogen, aryl, C₁₋₈ alkyl, C₃₋₈ cycloalkyl, C₃₋₈cycloheteroalkyl, aryl C₁₋₆alkyl, amino C₀₋₆alkyl, C₁₋₆ alkylaminoC₀₋₆alkyl, (C₁₋₆ alkyl)₂amino C₀₋₆alkyl, aryl C₀₋₆ alkylamino C₀₋₆alkyl,(aryl C₀₋₆ alkyl)₂amino C₀₋₆alkyl, C₁₋₆ alkylthio, aryl C₀₋₆alkylthio,C₁₋₆ alkylsulfinyl, aryl C₀₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, arylC₀₋₆alkylsulfonyl, C₁₋₆ alkoxy C₀₋₆alkyl, aryl C₀₋₆ alkoxy C₀₋₆alkyl,hydroxycarbonyl C₀₋₆alkyl, C₁₋₆ alkoxycarbonyl C₀₋₆alkyl, aryl C₀₋₆alkoxycarbonyl C₀₋₆alkyl, hydroxycarbonyl C₁₋₆ alkyloxy, hydroxyC₀₋₆alkyl, cyano, nitro, perfluoroC₁₋₄alkyl, perfluoroC₁₋₄alkoxy, oxo,C₁₋₆ alkylcarbonyloxy, aryl C₀₋₆alkylcarbonyloxy, C₁₋₆alkylcarbonylamino, aryl C₀₋₆ alkylcarbonylamino, C₁₋₆alkylsulfonylamino, aryl C₀₋₆alkylsulfonylamino, C₁₋₆alkoxycarbonylamino, aryl C₀₋₆ alkoxycarbonylamino,C₁₋₆alkylaminocarbonylamino, aryl C₀₋₆alkylaminocarbonylamino,(C₁₋₆alkyl)₂ aminocarbonylamino, (aryl C₀₋₆alkyl)₂ aminocarbonylamino,(C₁₋₆alkyl)₂ aminocarbonyloxy, (aryl C₀₋₆alkyl)₂ aminocarbonyloxy, andC₀₋₆alkylcarbonyl C₀₋₆ alkyl. Examples of aryl include, but are notlimited to, phenyl, naphthyl, pyridyl, pyrrolyl, pyrazolyl, pyrazinyl,pyrimidinyl, imidazolyl, benzimidazolyl, benzthiazolyl, benzoxazolyl,indolyl, thienyl, furyl, dihydrobenzofuryl, benzo(1,3)dioxolanyl,benzo(1,4)dioxanyl, oxazolyl, isoxazolyl, thiazolyl, quinolinyl,isothiazolyl, indanyl, isoquinolinyl, dihydroisoquinolinyl,tetrahydronaphthyridinyl, benzothienyl, imidazopyridinyl,tetrahydrobenzazepinyl, quinoxalinyl, imidazopyriridinyl,cyclopentenopyridinyl, phthalazinyl, tetrahydroquinolinyl, oxindolyl,isoquinolinyl, imidazothiazolyl, dihydroimidazothiazolyl, tetrazolyl,triazolyl, pyridazinyl, piperidinyl, piperazinyl, oxadiazolyl,thiadiazolyl, triazinyl, indazolyl, indazolinone, dihydrobenzofuranyl,phthalide, phthalimide, coumarin, chromone, tetrahydroisoquindine,naphthyridinyl, tetrahydronaphthyridinyl, isoindolinyl,triazanaphthalinyl, pteridinyl, and purinyl, which are eitherunsubstituted or substituted with one or more groups independentlyselected from hydrogen, halogen, aryl, C₁₋₈ alkyl, C₃₋₈ cycloalkyl, C₃₋₈cycloheteroalkyl, aryl C₁₋₆alkyl, amino C₀₋₆alkyl, C₁₋₆ alkylaminoC₀₋₆alkyl, (C₁₋₆ alkyl)₂amino C₀₋₆alkyl, aryl C₀₋₆ alkylamino C₀₋₆alkyl,(aryl C₀₋₆ alkyl)₂amino C₀₋₆alkyl, C₁₋₆ alkylthio, aryl C₀₋₆alkylthio,C₁₋₆ alkylsulfinyl, aryl C₀₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, arylC₁₋₆alkylsulfonyl, C₁₋₆ alkoxy C₀₋₆alkyl, aryl C₀₋₆ alkoxy C₀₋₆alkyl,hydroxycarbonyl C₀₋₆alkyl, C₁₋₆ alkoxycarbonyl C₀₋₆alkyl, aryl C₀₋₆alkoxycarbonyl C₀₋₆alkyl, hydroxycarbonyl C₁₋₆ alkyloxy, hydroxyC₀₋₆alkyl, cyano, nitro, perfluoroC₁₋₄alkyl, perfluoroC₁₋₄alkoxy, oxo,C₁₋₆ alkylcarbonyloxy, aryl C₀₋₆alkylcarbonyloxy, C₁₋₆alkylcarbonylamino, aryl C₀₋₆ alkylcarbonylamino, C₁₋₆alkylsulfonylamino, aryl C₀₋₆alkylsulfonylamino, C₁₋₆alkoxycarbonylamino, aryl C₀₋₆ alkoxycarbonylamino,C₁₋₆alkylaminocarbonylamino, aryl C₀₋₆alkylaminocarbonylamino,(C₁₋₆alkyl)₂ aminocarbonylamino, (aryl C₀₋₆alkyl)₂ aminocarbonylamino,(C₁₋₆alkyl)₂ aminocarbonyloxy, (aryl C₀₋₆alkyl)₂ aminocarbonyloxy,C₀₋₆alkylcarbonyl C₀₋₆alkyl and arylC₀₋₆alkylcarbonyl C₀₋₆alkyl. In oneembodiment of the present invention, aryl is selected from phenyl,pyridyl, pyrazolyl, benzamidazolyl, imidazolyl, furyl, napthyl, indolyl,indanyl, thienyl, pyrazinyl, benzothienyl,3,4-dihydro-1(1H)-isoquinolinyl, 1-8-tetrahydronaphthyridinyl,imidazo[1,2-a]pyridinyl, 2-oxo-2,3,4,5-tetrahydro-1H-benzo[B]azepinyl,quinoxalinyl, imidazo[1,2-a]pyrimidinyl, 2-3-cyclopentenopyridinyl,1-(2H)-phthalazinyl, 1,2,3,4-tetrahydroquinolinyl, oxindolyl,isoquinolinyl, imidazo[2,1-b][1,3]thiazolyl,2,3-dihydroimidazo[2,1-b][1,3]thiazolyl, and quinolinyl. Preferably, thearyl group is unsubstituted, mono-, di-, or tri-substituted with one tothree of the above-named substituents; more preferably, the aryl groupis unsubstituted, mono- or di-substituted with one to two of theabove-named substituents.

Whenever the term “alkyl” or “aryl” or either of their prefix rootsappears in a name of a substituent (e.g., aryl C₀₋₈ alkyl), it shall beinterpreted as including those limitations given above for “alkyl” and“aryl.” Designated numbers of carbon atoms (e.g., C₀₋₈) shall referindependently to the number of carbon atoms in an alkyl or cyclic alkylmoiety or to the alkyl portion of a larger substituent in which alkylappears as its prefix root.

The terms “arylalkyl” and “alkylaryl” include an alkyl portion wherealkyl is as defined above and to include an aryl portion where aryl isas defined above. Examples of arylalkyl include, but are not limited to,benzyl, fluorobenzyl, chlorobenzyl, phenylethyl, phenylpropyl,fluorophenylethyl, chlorophenylethyl, thienylmethyl, thienylethyl, andthienylpropyl. Examples of alkylaryl include, but are not limited to,toluene, ethylbenzene, propylbenzene, methylpyridine, ethylpyridine,propylpyridine and butylpyridine.

The term “halogen” shall include iodine, bromine, chlorine, andfluorine.

The term “oxy” means an oxygen (O) atom. The term “thio” means a sulfur(S) atom. The term “oxo” means “═O”. The term “carbonyl” means “C═O.”

When any variable (e.g., R³, R⁴, etc.) occurs more than one time in anyconstituent or in formula I, its definition on each occurrence isindependent of its definition at every other occurrence. Also,combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds.

Under standard nonmenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.For example, a C₁₋₅ alkylcarbonylamino C₁₋₆ alkyl substituent isequivalent to

In choosing compounds of the present invention, one of ordinary skill inthe art will recognize that the various substituents, i.e. R¹, R², R³,etc., are to be chosen in conformity with well-known principles ofchemical structure connectivity.

The term “substituted” shall be deemed to include multiple degrees ofsubstitution by a named substitutent. Where multiple substituentmoieties are disclosed or claimed, the substituted compound can beindependently substituted by one or more of the disclosed or claimedsubstituent moieties, singly or plurally. By independently substituted,it is meant that the (two or more) substituents can be the same ordifferent.

In one embodiment of the present invention X is selected from —O—, and—N(R⁴)—. In one class of this embodiment, X is selected from —O— and—NH—.

In another embodiment of the present invention, R¹ is selected fromhydrogen, C₁₋₃ alkyl, cyclopropyl and trifluoromethyl. In one class ofthe present invention, R¹ is selected from hydrogen, methyl, cyclopropyland trifluoromethyl. In one subclass of this class of the invention, R¹is selected from hydrogen, methyl, and trifluoromethyl.

In yet another embodiment of the present invention, R² is selected from:

-   -   (1) hydrogen,    -   (2) C₁₋₈ alkyl,    -   (3) C₃₋₈ cycloalkyl,    -   (4) C₃₋₈ cycloheteroalkyl,    -   (5) C₃₋₈ cycloalkyl-C₁₋₆ alkyl,    -   (6) C₃₋₈ cycloheteroalkyl-C₁₋₆ alkyl,    -   (7) aryl,    -   (8) aryl-C₁₋₆ allyl,    -   (9) amino,    -   (10) amino-C₁₋₆ alkyl,    -   (11) C₁₋₃ acylamino,    -   (12) C₁₋₃ acylamino-C₁₋₆ alkyl,    -   (13) (C₁₋₆ alkyl)_(n) amino,    -   (14) C₃₋₆ cycloalkyl-C₀₋₂ alkylamino,    -   (15) (C₁₋₆ alkyl)_(n) amino-C₁₋₆ alkyl,    -   (16) C₁₋₆ alkoxy,    -   (17) C₁₋₄ alkoxy-C₁₋₆ alkyl,    -   (18) hydroxycarbonyl,    -   (19) hydroxycarbonyl-C₁₋₆ alkyl,    -   (20) C₁₋₃ alkoxycarbonyl,    -   (21) C₁₋₃ alkoxycarbonyl-C₁₋₆ alkyl,    -   (22) hydroxy,    -   (23) hydroxy-C₁₋₆ alkyl,    -   (24) nitro,    -   (25) cyano,    -   (26) trifluoromethyl,    -   (27) trifluoromethoxy,    -   (28) trifluoroethoxy,    -   (29) C₁₋₈ alkyl-S(O)_(p)—,    -   (30) (C₁₋₈ alkyl)_(p)aminocarbonyl,    -   (31) C₁₋₈ alkyloxycarbonylamino,    -   (32) (C₁₋₈ alkyl)_(n) aminocarbonyloxy,    -   (33) (aryl C₁₋₃ alkyl)_(n) amino,    -   (34) (aryl)_(n) amino,    -   (35) aryl-C₁₋₃ alkylsulfonylamino, and    -   (36) C₁₋₈ alkylsulfonylamino;        wherein the alkyl groups are either unsubstituted or substituted        with one to three R⁵ substituents and wherein any of the aryl,        cycloalkyl, or cycloheteroalkyl groups are either unsubstituted        or substituted with one to three R⁶ substituents. In one class        of this embodiment of the present invention, R² is selected        from:    -   (1) hydrogen,    -   (2) C₁₋₆ alkyl,    -   (3) C₃₋₈ cycloalkyl,    -   (4) C₄₋₆ cycloheteroalkyl,    -   (5) C₃₋₈ cycloalkyl-C₁₋₃ alkyl,    -   (6) C₄₋₆ cycloheteroalkyl-C₁₋₃ alkyl,    -   (7) phenyl,    -   (8) phenyl-C₁₋₃ alkyl,    -   (9) amino,    -   (10) amino-C₁₋₃ alkyl,    -   (11) C₁₋₃ acylamino,    -   (12) C₁₋₃ acylamino-C₁₋₃ alkyl,    -   (13) (C₁₋₃ alkyl)_(n) amino,    -   (14) C₃₋₆ cycloalkyl-C₀₋₂ alkylamino,    -   (15) (C₁₋₃ alkyl)_(n) amino-C₁₋₆ alkyl,    -   (16) C₁₋₆ alkoxy,    -   (17) C₁₋₃ alkoxy-C₁₋₆ alkyl,    -   (18) hydroxycarbonyl,    -   (19) hydroxycarbonyl-C₁₋₆ alkyl,    -   (20) C₁₋₃ alkoxycarbonyl,    -   (21) C₁₋₃ alkoxycarbonyl-C₁₋₆ alkyl,    -   (22) hydroxy,    -   (23) hydroxy-C₁₋₆ alkyl,    -   (24) nitro,    -   (25) cyano,    -   (26) trifluoromethyl,    -   (27) trifluoromethoxy,    -   (28) trifluoroethoxy,    -   (29) C₁₋₆ alkyl-S(O)_(p)—,    -   (30) (C₁₋₆ alkyl)_(p) aminocarbonyl,    -   (31) C₁₋₃ alkyloxycarbonylamino,    -   (32) (C₁₋₃ alkyl)_(n) aminocarbonyloxy,    -   (33) (aryl C₁₋₃ alkyl)_(n) amino,    -   (34) (aryl)₁₋₂ amino,    -   (35) aryl-C₁₋₃ alkylsulfonylamino, and    -   (36) C₁₋₆ alkylsulfonylamino;        wherein any of the alkyl groups are either unsubstituted or        substituted with one to three R⁵ substituents; and wherein any        of the aryl, cycloalkyl, or cycloheteroalkyl groups are        unsubstituted or substituted with one to three R⁶ substituents.        In one subclass of this class of the invention, R² is selected        from hydrogen, C₁₋₈ alkyl, cyclopropyl, cyclohexyl, piperidinyl,        pyrrolidinyl, azetidinyl, morpholinyl, piperazinyl,        cyclopropylmethyl, cyclopropylethyl, cyclopropyl-propyl,        cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl,        piperidinylmethyl pyrrolidinylmethyl, azetidinylmethyl,        morpholinylmethyl, piperazinylmethyl, piperidinylethyl,        pyrrolidinylethyl, morpholinylethyl, piperazinylethyl,        piperidinylpropyl, morpholinylpropyl, piperazinylpropyl, phenyl,        benzyl, phenylethyl, phenylpropyl, hydroxy, methoxy,        trifluoromethyl, trifluoromethyoxy, and trifluoroethoxy; wherein        any of the alkyl groups of R² are either unsubstituted or        substituted with one to three R⁵ substituents; and wherein any        of the aryl, cycloalkyl, or cycloheteroalkyl groups in R² are        optionally substituted with one to three R⁶ substituents.

In yet another subclass of this class of the invention, R² is selectedfrom hydrogen, C₁₋₃ alkyl, benzyl, and cyclopropylmethyl. In stillanother subclass of this class of the invention, R² is selected fromhydrogen, methyl, benzyl, and cyclopropylmethyl.

In one embodiment of the present invention, R³ is selected fromhydrogen, C₁₋₈ alkyl, and trifluoromethyl. In one class of thisembodiment of the present invention, R³ is selected from hydrogen,methyl and trifluoromethyl. In one subclass of this class of theinvention, R³ is selected from hydrogen and methyl.

In another embodiment of the present invention, R² and R³ together withthe carbon atom to which they are attached form a carbonyl group, orjoin to form a 3- to 6-membered spiro-carbocyclic ring; wherein thealkyl groups in R² and R³ are either unsubstituted or substituted withone to three R⁵ substituents and wherein any of the aryl, cycloalkyl, orcycloheteroalkyl groups in R³ are either unsubstituted or substitutedwith one to three R⁶ substituents.

In one class of this embodiment of the present invention, R² and R³,together with the carbon to which they are attached, join to form aspiro-cyclopropyl ring. In another class of this embodiment of thepresent invention, R² and R³, together with the carbon to which they areattached, join to form a carbonyl group.

In yet another embodiment of the present invention, R⁴ is selected from:

-   -   (1) hydrogen,    -   (2) aryl,    -   (3) aminocarbonyl,    -   (4) C₃₋₈ cycloalkyl,    -   (5) amino C₁₋₆ alkyl,    -   (6) (aryl)_(p)aminocarbonyl,    -   (7) (aryl C₁₋₅ alkyl)_(p)aminocarbonyl,    -   (8) hydroxycarbonyl C₁₋₆ alkyl,    -   (9) C₁₋₈ alkyl,    -   (10) perfluoro C₁₋₈ alkyl,    -   (11) aryl C₁₋₆ alkyl,    -   (12) (C₁₋₆ alkyl)_(p)amino C₂₋₆ alkyl,    -   (13) (aryl C₁₋₆ alkyl)_(p)amino C₂₋₆ alkyl,    -   (14) C₁₋₈ alkylsulfonyl,    -   (15) C₁₋₈ alkoxycarbonyl,    -   (16) aryloxycarbonyl,    -   (17) aryl C₁₋₈ alkoxycarbonyl,    -   (18) C₁₋₈ alkylcarbonyl,    -   (19) arylcarbonyl,    -   (20) aryl C₁₋₆ alkylcarbonyl,    -   (21) (C₁₋₈ alkyl)_(p)aminocarbonyl,    -   (22) aminosulfonyl,    -   (23) C₁₋₈ alkylaminosulfonyl,    -   (24) (aryl)_(p)aminosulfonyl,    -   (25) (aryl C₁₋₈ alkyl)_(p)aminosulfonyl,    -   (26) arylsulfonyl,    -   (27) aryl C₁₋₆ alkylsulfonyl,    -   (28) C₁₋₆ alkylthiocarbonyl,    -   (29) arylthiocarbonyl, and    -   (30) aryl C₁₋₆ alkylthiocarbonyl,        wherein any of the alkyl groups of R⁴ are either unsubstituted        or substituted with one to three R⁵ substituents and wherein any        of the aryl, cycloalkyl, or cycloheteroalkyl groups in R⁴ are        optionally substituted with one to three R⁶ substituents.

In one class of this embodiment of the present invention, R⁴ is selectedfrom:

-   -   (1) hydrogen,    -   (2) aryl,    -   (3) C₁₋₈ alkyl,    -   (4) perfluoro C₁₋₈ alkyl, and    -   (5) aryl C₁₋₆ alkyl;        wherein any of the alkyl groups of are either unsubstituted or        substituted with one to three R⁵ substituents; and wherein any        of the aryl groups are either unsubstituted or substituted with        one to three R⁶ substituents.

In one subclass of this class of the present invention, R⁴ is selectedfrom hydrogen, methyl, ethyl, cyclopropyl, trifluoromethyl, andperfluoroethyl. In yet another subclass of this class of the presentinvention, R⁴ is selected from hydrogen, methyl, cyclopropyl,andtrifluoromethyl. In still another subclass of this class of the presentinvention, R⁴ is selected from hydrogen and methyl.

In one embodiment of the present invention, each R⁵ is independentlyselected from:

-   -   (1) halogen,    -   (2) C₁₋₈ alkyl,    -   (3) C₃₋₈ cycloalkyl,    -   (4) C₃₋₈ cycloheteroalkyl,    -   (5) C₃₋₈ cycloalkyl-C₁₋₆ alkyl,    -   (6) C₃₋₈ cycloheteroalkyl-C₁₋₆ alkyl,    -   (7) aryl,    -   (8) aryl-C₁₋₆ alkyl,    -   (9) amino,    -   (10) amino-C₁₋₆ alkyl,    -   (11) C₁₋₃ acylamino,    -   (12) C₁₋₃ acylamino-C₁₋₆ alkyl,    -   (13) (C₁₋₆ alkyl)_(n) amino,    -   (14) C₃₋₆ cycloalkyl-C₀₋₂ alkylamino,    -   (15) (C₁₋₆ alkyl)_(n) amino-C₁₋₆ alkyl,    -   (16) C₁₋₆ alkoxy,    -   (17) C₁₋₄ alkoxy-C₁₋₆ alkyl,    -   (18) hydroxycarbonyl,    -   (19) hydroxycarbonyl-C₁₋₆ alkyl,    -   (20) C₁₋₃ alkoxycarbonyl,    -   (21) C₁₋₃ alkoxycarbonyl-C₁₋₆ alkyl,    -   (22) hydroxy,    -   (23) hydroxy-C₁₋₆ alkyl,    -   (24) nitro,    -   (25) cyano,    -   (26) trifluoromethyl,    -   (27) trifluoromethoxy,    -   (28) trifluoroethoxy,    -   (29) C₁₋₈ alkyl-S(O)_(p),    -   (30) (C₁₋₈ alkyl)_(p)aminocarbonyl,    -   (31) C₁₋₈ alkyloxycarbonylamino,    -   (32) (C₁₋₈ alkyl)_(n) aminocarbonyloxy,    -   (33) (aryl C₁₋₃ alkyl)_(n) amino,    -   (34) (aryl)_(n) amino,    -   (35) aryl-C₁₋₃ alkylsulfonylamino, and    -   (36) C₁₋₈ alkylsulfonylamino.

In one class of this embodiment of the present invention, each R⁵ isindependently selected from:

-   -   (1) halogen,    -   (2) C₁₋₈ alkyl,    -   (3) C₃₋₈ cycloalkyl,    -   (4) C₃₋₈ cycloheteroalkyl,    -   (5) C₃₋₈ cycloalkyl-C₁₋₆ alkyl,    -   (6) aryl,    -   (7) amino,    -   (8) C₁₋₃ acylamino,    -   (9) (C₁₋₆ alkyl)_(n) amino,    -   (10) C₃₋₆ cycloalkyl-C₀₋₂ alkylamino,    -   (11) C₁₋₆ alkoxy,    -   (12) hydroxycarbonyl,    -   (13) hydroxy,    -   (14) cyano,    -   (15) trifluoromethyl,    -   (16) trifluoromethoxy,    -   (17) trifluoroethoxy,    -   (18) (C₁₋₈ alkyl)_(p)aminocarbonyl,    -   (19) C₁₋₈ alkyloxycarbonylamino,    -   (20) (C₁₋₈ alkyl)_(n) aminocarbonyloxy,    -   (21) (aryl C₁₋₃ alkyl)_(n) amino, and    -   (22) (aryl)_(n) amino.

In another class of the present invention, each R⁵ is independentlyselected from:

-   -   (1) C₁₋₈ alkyl,    -   (2) C₃₋₈ cycloalkyl,    -   (3) C₃₋₈ cycloheteroalkyl,    -   (4) C₃₋₈ cycloalkyl-C₁₋₆ alkyl,    -   (5) C₃₋₈ cycloheteroalkyl-C₁₋₆ alkyl,    -   (6) aryl,    -   (7) aryl-C₁₋₆ alkyl,    -   (8) amino,    -   (9) amino-C₁₋₆ alkyl,    -   (10) C₁₋₃ acylamino,    -   (11) C₁₋₃ acylamino-C₁₋₆ alkyl,    -   (12) (C₁₋₆ alkyl)_(n) amino,    -   (13) C₃₋₆ cycloalkyl-C₀₋₂ alkylamino,    -   (14) (C₁₋₆ alkyl)_(n) amino-C₁₋₆ alkyl,    -   (15) C₁₋₆ alkoxy,    -   (16) C₁₋₄ alkoxy-C₁₋₆ alkyl,    -   (17) hydroxycarbonyl,    -   (18) hydroxycarbonyl-C₁₋₆ alkyl,    -   (19) C₁₋₃ alkoxycarbonyl,    -   (20) C₁₋₃ alkoxycarbonyl-C₁₋₆ alkyl,    -   (21) hydroxy,    -   (22) hydroxy-C₁₋₆ alkyl,    -   (23) nitro,    -   (24) cyano,    -   (25) trifluoromethyl,    -   (26) trifluoromethoxy,    -   (27) trifluoroethoxy,    -   (28) C₁₋₈ alkyl-S(O)_(p),    -   (29) (C₁₋₈ alkyl)_(p)aminocarbonyl,    -   (30) C₁₋₈ alkyloxycarbonylamino,    -   (31) (C₁₋₈ alkyl)_(n) aminocarbonyloxy,    -   (32) (aryl C₁₋₃ alkyl)n amino,    -   (33) (aryl)_(n) amino,    -   (34) aryl-C₁₋₃ alkylsulfonylamino, and    -   (35) C₁₋₈ alkylsulfonylamino.

In one subclass of this class of this embodiment, each R⁵ isindependently selected from:

-   -   (1) C₁₋₈ alkyl,    -   (2) C₃₋₈ cycloalkyl,    -   (3) C₃₋₈ cycloheteroalkyl,    -   (4) C₃₋₈ cycloalkyl-C₁₋₆ alkyl,    -   (5) aryl,    -   (6) amino,    -   (7) C₁₋₃ acylamino,    -   (8) (C₁₋₆ alkyl)_(n) amino,    -   (9) C₃₋₆ cycloalkyl-C₀₋₂ alkylamino,    -   (10) C₁₋₆ alkoxy,    -   (11) hydroxycarbonyl,    -   (12) hydroxy,    -   (13) cyano,    -   (14) trifluoromethyl,    -   (15) trifluoromethoxy,    -   (16) trifluoroethoxy,    -   (17) (C₁₋₈ alkyl)_(p)aminocarbonyl,    -   (18) C₁₋₈ alkyloxycarbonylamino,    -   (19) (C₁₋₈ alkyl)_(n) aminocarbonyloxy,    -   (20) (aryl C₁₋₃ alkyl)_(n) amino, and    -   (21) (aryl)_(n) amino.

In one subclass of this class of this embodiment, each R⁵ isindependently selected from:

-   -   (1) C₃₋₈ cycloalkyl,    -   (2) C₃₋₈ cycloheteroalkyl,    -   (3) C₃₋₈ cycloalkyl-C₁₋₆ alkyl,    -   (4) aryl,    -   (5) amino,    -   (6) C₁₋₃ acylamino,    -   (7) (C₁₋₆ alkyl)_(n) amino,    -   (8) C₃₋₆ cycloalkyl-C₀₋₂ alkylamino,    -   (9) C₁₋₆ alkoxy,    -   (10) hydroxycarbonyl,    -   (11) hydroxy,    -   (12) cyano,    -   (13) trifluoromethyl,    -   (14) trifluoromethoxy,    -   (15) trifluoroethoxy,    -   (16) (C₁₋₈ alkyl)_(p)aminocarbonyl,    -   (17) C₁₋₈ alkyloxycarbonylamino,    -   (18) (C₁₋₈ alkyl)_(n) aminocarbonyloxy,    -   (19) (aryl C₁₋₃ alkyl)_(n) amino, and    -   (20) (aryl)_(n) amino.

In still another embodiment of the present invention, each R⁶ isindependently selected from:

-   -   (1) halogen,    -   (2) aryl,    -   (3) C₁₋₈ alkyl,    -   (4) C₃₋₈ cycloalkyl,    -   (5) C₃₋₈ cycloheteroalkyl,    -   (6) aryl C₁₋₆alkyl,    -   (7) amino C₀₋₆alkyl,    -   (8) C₁₋₆ alkylamino C₀₋₆alkyl,    -   (9) (C₁₋₆ alkyl)₂amino C₀₋₆alkyl,    -   (10) aryl C₁₋₆ alkylamino C₀₋₆alkyl,    -   (11) (aryl C₀₋₆ alkyl)₂amino C₀₋₆alkyl,    -   (12) C₁₋₆ alkylthio,    -   (13) aryl C₀₋₆alkylthio,    -   (14) C₁₋₆ alkylsulfinyl,    -   (15) aryl C₀₋₆alkylsulfinyl,    -   (16) C₁₋₆ alkylsulfonyl,    -   (17) aryl C₀₋₆alkylsulfonyl,    -   (18) C₁₋₆ alkoxy C₀₋₆alkyl,    -   (19) aryl C₀₋₆ alkoxy C₁₋₆alkyl,    -   (20) hydroxycarbonyl C₀₋₆alkyl,    -   (21) C₁₋₆ alkoxycarbonyl C₀₋₆alkyl,    -   (22) aryl C₀₋₆ alkoxycarbonyl C₀₋₆alkyl,    -   (23) hydroxycarbonyl C₁₋₆ alkyloxy,    -   (24) hydroxy C₀₋₆alkyl,    -   (25) cyano,    -   (26) nitro,    -   (27) perfluoroC₁₋₄alkyl,    -   (28) perfluoroC₁₋₄alkoxy,    -   (29) oxo,    -   (30) C₁₋₆ alkylcarbonyloxy,    -   (31) aryl C₀₋₆alkylcarbonyloxy,    -   (32) alkyl C₁₋₆ carbonylamino,    -   (33) aryl C₀₋₆ alkylcarbonylamino,    -   (34) C₁₋₆ alkylsulfonylamino,    -   (35) aryl C₀₋₆alkylsulfonylamino,    -   (36) C₁₋₆ alkoxycarbonylamino,    -   (37) aryl C₀₋₆ alkoxycarbonylamino,    -   (38) C₁₋₆alkylaminocarbonylamino,    -   (39) aryl C₀₋₆alkylaminocarbonylamino,    -   (40) (C₁₋₆alkyl)₂ aminocarbonylamino,    -   (41) (aryl C₀₋₆alkyl)₂ aminocarbonylamino,    -   (42) (C₁₋₆alkyl)₂ aminocarbonyloxy,    -   (43) (aryl C₀₋₆alkyl)₂ aminocarbonyloxy,    -   (44) C₀₋₆alkylcarbonyl C₀₋₆alkyl, and    -   (45) aryl C₀₋₆alkylcarbonyl C₀₋₆alkyl.

In one class of this embodiment of the present invention, each R⁶ isindependently selected from:

-   -   (1) halogen,    -   (2) phenyl,    -   (3) C₁₋₃ alkyl,    -   (4) C₄₋₆ cycloheteroalkyl,    -   (5) phenyl C₁₋₃alkyl,    -   (6) amino C₀₋₃alkyl,    -   (7) C₁₋₃ alkylamino C₀₋₃alkyl,    -   (8) (C₁₋₃ alkyl)₂amino C₀₋₃alkyl,    -   (9) phenyl C₀₋₃alkylamino C₀₋₃alkyl,    -   (10) (phenyl C₀₋₃ alkyl)₂amino C₀₋₃alkyl,    -   (11) C₁₋₃ alkoxy C₀₋₃alkyl,    -   (12) aryl C₀₋₃ alkoxy C₀₋₃alkyl,    -   (13) hydroxycarbonyl C₀₋₃alkyl,    -   (14) C₁₋₃ alkoxycarbonyl C₀₋₃alkyl,    -   (15) phenyl C₀₋₃ alkoxycarbonyl C₀₋₃alkyl,    -   (16) hydroxy C₀₋₃alkyl,    -   (17) cyano,    -   (18) trifluoromethyl, and    -   (19) trifluoromethoxy.

In one subclass of this class of the present invention, each R⁶ isindependently selected from:

-   -   (1) halogen,    -   (2) phenyl,    -   (3) methyl,    -   (4) C₄₋₆ cycloheteroalkyl,    -   (5) phenyl C₁₋₃alkyl,    -   (6) amino C₀₋₃alkyl,    -   (7) C₁₋₃ alkylamino C₀₋₃alkyl,    -   (8) (C₁₋₃ alkyl)₂amino C₀₋₃alkyl,    -   (9) phenyl C₀₋₃alkylamino C₀₋₃alkyl,    -   (10) C₁₋₃ alkoxy C₀₋₃alkyl;    -   (11) aryl C₀₋₃ alkoxy C₀₋₃alkyl,    -   (12) hydroxycarbonyl,    -   (13) C₁₋₃ alkoxycarbonyl C₀₋₃alkyl,    -   (14) hydroxy    -   (15) methoxy,    -   (16) cyano,    -   (17) trifluoromethyl, and    -   (18) trifluoromethoxy.

Particular compounds of structural formula (I) include:

-   4-(trifluoromethyl)-7,8,9,10-tetrahydrochromeno[7,6-b]azepin-2(6H)-one,-   4-(trifluoromethyl)-1,6,7,8,9,10-hexahydro-2H-azepino[3,2-g]quinolin-2-one,-   1,6,7,8,9,10-hexahydro-2H-azepino[3,2-g]quinolin-2-one,-   8-(R)-methyl-4-(trifluoromethyl)-7,8,9,10-tetrahydrochromeno[7,6-b]azepin-2(6H)-one,-   8-(S)-methyl-4-(trifluoromethyl)-7,8,9,10-tetrahydrochromeno[7,6-b]azepin-2(6H)-one,-   8-spirocyclopropyl-4-(trifluoromethyl)-7,8,9,10-tetrahydrochromeno[7,6-b]azepin-2(6H)-one,-   8-(R,S)-propyl-4-(trifluoromethyl)-7,8,9,10-tetrahydrochromeno[7,6-b]azepin-2(6H)-one,-   8-(R,S)-dimethyl-4-(trifluoromethyl)-7,8,9,10-tetrahydrochromeno[7,6-b]azepin-2(6H)-one,-   8-(R,S)-benzyl-4-(trifluoromethyl)-7,8,9,10-tetrahydrochromeno[7,6-b]azepin-2(6H)-one,-   8-(R,S)-ethyl-4-(trifluoromethyl)-7,8,9,10-tetrahydrochromeno[7,6-b]azepin-2(6H)-one,-   8-(R,S)-cyclopropylmethyl-4-(trifluoromethyl)-7,8,9,10-tetrahydrochromeno[7,6-b]azepin-2(6H)-one,-   4,8-(R,S)-dimethyl-7,8,9,10-tetrahydrochromeno[7,6-b]azepin-2(6H)-one,    and-   4-methyl-8-(R,S)-propyl-7,8,9,10-tetrahydrochromeno[7,6-b]azepin-2(6H)-one,    and pharmaceutically acceptable salts thereof.

Compounds of the present invention, which may be prepared in accordancewith the methods described herein, have been found to be tissueselective modulators of the androgen receptor (SARMs). In one aspect,compounds of the present invention may be useful to agonize the androgenreceptor in a patient, and in particular to agonize the androgenreceptor in bone and/or muscle tissue and antagonize the androgenreceptor in the prostate of a male patient or in the uterus of a femalepatient and agonize the androgen receptor in bone and/or muscle tissue.In another aspect of the present invention, compounds of structuralformula I may be useful to agonize the androgen receptor in bone and/ormuscle tissue and antagonize the androgen receptor in the prostate of amale patient or in the uterus or skin of a female patient. The agonismin bone can be assayed through stimulation of bone formation in therodent model of osteoporosis, and the antagonism in the prostate can beassayed through observation of minimal effects on prostate growth incastrated rodents and antagonism of prostate growth induced by ARagonists, as detailed in the Examples.

In a further aspect of the present invention are compounds of structuralformula I that antagonize the androgen receptor in the prostate of amale patient or in the uterus of a female patient, but not inhair-growing skin or vocal cords, and agonize the androgen receptor inbone and/or muscle tissue, but not in organs which control blood lipidlevels (e.g. liver). These compounds are useful in the treatment ofconditions caused by androgen deficiency or which can be ameliorated byandrogen administration, including: osteoporosis, periodontal disease,bone fracture, bone damage following bone reconstructive surgery,sarcopenia, frailty, aging skin, male hypogonadism, female sexualdysfunction, post-menopausal symptoms in women, atherosclerosis,hypercholesterolemia, hyperlipidemia, aplastic anemia and otherhematopoietic disorders, arthritis and joint repair, alone or incombination with other active agents. In addition, these compounds areuseful as pharmaceutical composition ingredients alone and incombination with other active agents.

The compounds of the present invention may be used to treat conditionswhich are caused by androgen deficiency or which can be ameliorated byandrogen administration, including, but not limited to: osteoporosis,periodontal disease, bone fracture, bone damage following bonereconstructive surgery, sarcopenia, frailty, aging skin, malehypogonadism, female sexual dysfunction, post-menopausal symptoms inwomen, atherosclerosis, hypercholesterolemia, hyperlipidemia, aplasticanemia and other hematopoietic disorders, arthritis and joint repair,alone or in combination with other active agents. Treatment is effectedby administration of a therapeutically effective amount of the compoundof structural formula I to the patient in need of such treatment.

The compounds of the present invention may be used in the treatment ofprostate cancer, either as sole therapy, or, preferably as adjuncts totraditional androgen depletion therapy in the treatment of prostatecancer to restore bone, minimize bone loss, and maintain bone mineraldensity. In this manner, they may be employed together with traditionalandrogen deprivation therapy, including GnRH agonists/antagonists suchas leuprolide. It is also possible that the compounds of structuralformula I may be used in combination with antiandrogens such asflutamide, hydroxy-flutamide (the active form of flutamide), andCasodex™ (the trademark for ICI-176,334 from Imperial ChemicalIndustries PLC, presently Astra-Zeneca) in the treatment of prostatecancer.

Further, the compounds of the present invention may also be employed inthe treatment of pancreatic cancer, either for their androgen antagonistproperties or as an adjunct to an antiandrogen such as flutamide,hydroxy-flutamide (the active form of flutamide), and Casodex™ (thetrademark for ICI-176,334).

Compounds of structural formula I have minimal negative effects on lipidmetabolism, thus considering their tissue selective androgen agonismlisted above, the compounds in this invention are ideal for hormonereplacement therapy in hypogonadic (androgen deficient) men.

“Male sexual dysfunction” includes impotence, loss of libido, anderectile dysfunction.

“Erectile dysfunction” is a disorder involving the failure of a malemammal to achieve erection, ejaculation, or both. Symptoms of erectiledysfunction include an inability to achieve or maintain an erection,ejaculatory failure, premature ejaculation, or inability to achieve anorgasm. An increase in erectile dysfunction and sexual dysfunction canhave numerous underlying causes, including but not limited to (1) aging,(b) an underlying physical dysfunction, such as trauma, surgery, andperipheral vascular disease, and (3) side-effects resulting from drugtreatment, depression, and other CNS disorders.

“Female sexual dysfunction” can be seen as resulting from multiplecomponents including dysfunction in desire, sexual arousal, sexualreceptivity, and orgasm related to disturbances in the clitoris, vagina,periurethral glans, and other trigger points of sexual function. Inparticular, anatomic and functional modification of such trigger pointsmay diminish the orgasmic potential in breast cancer and gynecologiccancer patients. Treatment of female sexual dysfunction with an SARMcompound of the present invention can result in improved blood flow,improved lubrication, improved sensation, facilitation of reachingorgasm, reduction in the refractory period between orgasms, andimprovements in arousal and desire. In a broader sense, “female sexualdysfunction” also incorporates sexual pain, premature labor, anddysmenorrhea.

Additionally, compounds in this invention can increase the number ofblood cells, such as red blood cells and platelets and can be used fortreatment of hematopoietic disorders such as aplastic anemia.

Representative compounds of the present invention typically displaysubmicromolar affinity for the androgen receptor. Compounds of thisinvention are therefore useful in treating mammals suffering fromdisorders related to androgen receptor function. Pharmacologicallyeffective amounts of the compound, including the pharmaceuticallyeffective salts thereof, are administered to the mammal, to treatdisorders related to androgen receptor function, or which can beimproved by the addition of additional androgen, such as osteoporosis,periodontal disease, bone fracture, bone damage following bonereconstructive surgery, sarcopenia, frailty, aging skin, malehypogonadism, female sexual dysfunction, post-menopausal symptoms inwomen, atherosclerosis, hypercholesterolemia, hyperlipidemia, aplasticanemia and other hematopoietic disorders, pancreatic cancer, renalcancer, prostate cancer, arthritis and joint repair. In addition, thecompounds of the present invention are useful in treating osteoporosisand/or bone weakening induced by glucocorticoid administration.

It is generally preferable to administer compounds of the presentinvention as enantiomerically pure formulations. Racemic mixtures can beseparated into their individual enantiomers by any of a number ofconventional methods. These include chiral chromatography,derivatization with a chiral auxilIary followed by separation bychromatography or crystallization, and fractional crystallization ofdiastereomeric salts.

As used herein, a compound that binds to an intracellular receptor, suchas the androgen receptor, and mimics the effect of the natural ligand isreferred to as an “agonist”; whereas, a compound that inhibits theeffect of the natural ligand is called an “antagonist.” The term “tissueselective androgen receptor modulator” refers to to an androgen receptorligand that mimics the action of the natural ligand in some tissues butnot in others.

The term “pharmaceutically acceptable salt” is intended to include allacceptable salts such as acetate, lactobionate, benzenesulfonate,laurate, benzoate, malate, bicarbonate, maleate, bisulfate, mandelate,bitartrate, mesylate, borate, methylbromide, bromide, methylnitrate,calcium edetate, methylsulfate, camsylate, mucate, carbonate, napsylate,chloride, nitrate, clavulanate, N-methylglucamine, citrate, ammoniumsalt, dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate(embonate), estolate, palmitate, esylate, pantothenate, fumarate,phosphate/diphosphate, gluceptate, polygalacturonate, gluconate,salicylate, glutamate, stearate, glycollylarsanilate, sulfate,hexylresorcinate, subacetate, hydrabamine, succinate, hydrobromide,tannate, hydrochloride, tartrate, hydroxynaphthoate, teoclate, iodide,tosylate, isothionate, triethiodide, lactate, panoate, valerate, and thelike which can be used as a dosage form for modifying the solubility orhydrolysis characteristics or can be used in sustained release orpro-drug formulations.

The term “pharmaceutically effective amount” of an active ingredientsuch as a compound of structural formula I, is intended to encompassamounts of the ingredient that are therapeutically or prophylaticallyuseful in treating or preventing disease, particularly diseasesassociated with modulation of the Cannabinoid 1 receptor.

The term “therapeutically effective amount” means the amount thecompound of structural formula I that will elicit the biological ormedical response of a tissue, system, animal or human that is beingsought by the researcher, veterinarian, medical doctor or otherclinician.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts.

By “pharmaceutically acceptable” it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

The terms “administration of” and or “administering a” compound shouldbe understood to mean providing a compound of the invention or a prodrugof a compound of the invention to the individual in need of treatment.

The administration of the compound of structural formula I in order topractice the present methods of therapy is carried out by administeringan effective amount of the compound of structural formula I to thepatient in need of such treatment or prophylaxis. The need for aprophylactic administration according to the methods of the presentinvention is determined via the use of well known risk factors. Theeffective amount of an individual compound is determined, in the finalanalysis, by the physician in charge of the case, but depends on factorssuch as the exact disease to be treated, the severity of the disease andother diseases or conditions from which the patient suffers, the chosenroute of administration other drugs and treatments which the patient mayconcomitantly require, and other factors in the physician's judgment.

Generally, the daily dosage of the compound of structural formula I maybe varied over a wide range from 0.01 to 1000 mg per adult human perday. Most preferably, dosages range from 0.1 to 200 mg/day. For oraladministration, the compositions are preferably provided in the form oftablets containing 0.01 to 1000 mg, particularly 0.01, 0.05, 0.1, 0.5,1.0, 2.5, 3.0, 5.0, 6.0, 10.0, 15.0, 25.0, 50.0, 75, 100, 125, 150, 175,180, 200, 225, and 500 milligrams of the active ingredient for thesymptomatic adjustment of the dosage to the patient to be treated.

The dose may be administered in a single daily dose or the total dailydosage may be administered in divided doses of two, three or four timesdaily. Furthermore, based on the properties of the individual compoundselected for administration, the dose may be administered lessfrequently, e.g., weekly, twice weekly, monthly, etc. The unit dosagewill, of course, be correspondingly larger for the less frequentadministration.

When administered via intranasal routes, transdermal routes, by rectalor vaginal suppositories, or through a continual intravenous solution,the dosage administration will, of course, be continuous rather thanintermittent throughout the dosage regimen.

For the treatment of sexual dysfunction compounds of the presentinvention are given in a dose range of 0.001 milligram to about 100milligram per kilogram of body weight, preferably as a single doseorally or as a nasal spray.

Exemplifying the invention is a pharmaceutical composition comprisingany of the compounds described above and a pharmaceutically acceptablecarrier. Also exemplifying the invention is a pharmaceutical compositionmade by combining any of the compounds described above and apharmaceutically acceptable carrier. An illustration of the invention isa process for making a pharmaceutical composition comprising combiningany of the compounds described above and a pharmaceutically acceptablecarrier.

Formulations of the tissue selective androgen receptor modulatoremployed in the present method for medical use comprise the compound ofstructural formula I together with an acceptable carrier thereof andoptionally other therapeutically active ingredients. The carrier must bepharmaceutically acceptable in the sense of being compatible with theother ingredients of the formulation and not deleterious to therecipient subject of the formulation.

The present invention, therefore, further provides a pharmaceuticalformulation comprising the compound of structural formula I togetherwith a pharmaceutically acceptable carrier thereof.

The formulations include those suitable for oral, rectal, intravaginal,topical or parenteral (including subcutaneous, intramuscular andintravenous administration). Preferred are those suitable for oraladministration.

The formulations may be presented in a unit dosage form and may beprepared by any of the methods known in the art of pharmacy. All methodsinclude the step of bringing the active compound in association with acarrier which constitutes one or more ingredients. In general, theformulations are prepared by uniformly and intimately bringing theactive compound in association with a liquid carrier, a waxy solidcarrier or a finely divided solid carrier, and then, if needed, shapingthe product into desired dosage form.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets, tablets orlozenges, each containing a predetermined amount of the active compound;as a powder or granules; or a suspension or solution in an aqueousliquid or non-aqueous liquid, e.g., a syrup, an elixir, or an emulsion.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active compound in a free flowingform, e.g., a powder or granules, optionally mixed with accessoryingredients, e.g., binders, lubricants, inert diluents, disintegratingagents or coloring agents. Molded tablets may be made by molding in asuitable machine a mixture of the active compound, preferably inpowdered form, with a suitable carrier. Suitable binders include,without limitation, starch, gelatin, natural sugars such as glucose orbeta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium alginate, carboxymethyl-cellulose,polyethylene glycol, waxes and the like. Lubricants used in these dosageforms include, without limitation, sodium oleate, sodium stearate,magnesium stearate, sodium benzoate, sodium acetate, sodium chloride andthe like. Disintegrators include, without limitation, starch, methylcellulose, agar, bentonite, xanthan gum and the like.

Oral liquid forms, such as syrups or suspensions in suitably flavoredsuspending or dispersing agents such as the synthetic and natural gums,for example, tragacanth, acacia, methyl cellulose and the like may bemade by adding the active compound to the solution or suspension.Additional dispersing agents which may be employed include glycerin andthe like.

Formulations for vaginal or rectal administration may be presented as asuppository with a conventional carrier, i.e., a base that is nontoxicand nonirritating to mucous membranes, compatible with the compound ofstructural formula I, and is stable in storage and does not bind orinterfere with the release of the compound of structural formula I.Suitable bases include: cocoa butter (theobroma oil), polyethyleneglycols (such as carbowax and polyglycols), glycol-surfactantcombinations, polyoxyl 40 stearate, polyoxyethylene sorbitan fatty acidesters (such as Tween, Myrj, and Arlacel), glycerinated gelatin, andhydrogenated vegetable oils. When glycerinated gelatin suppositories areused, a preservative such as methylparaben or propylparaben may beemployed.

Topical preparations containing the active drug component can be admixedwith a variety of carrier materials well known in the art, such as,e.g., alcohols, aloe vera gel, allantoin, glycerine, vitamin A and Eoils, mineral oil, PPG2 myristyl propionate, and the like, to form,e.g., alcoholic solutions, topical cleansers, cleansing creams, skingels, skin lotions, and shampoos in cream or gel formulations.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine or phosphatidylcholines.

Compounds of the present invention may also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds of the present invention may alsobe coupled with soluble polymers as targetable drug carriers. Suchpolymers can include polyvinyl-pyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxy-ethylaspartamidephenol, or polyethylene-oxide polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

Formulations suitable for parenteral administration include formulationsthat comprise a sterile aqueous preparation of the active compound whichis preferably isotonic with the blood of the recipient. Suchformulations suitably comprise a solution or suspension of a compoundthat is isotonic with the blood of the recipient subject. Suchformulations may contain distilled water, 5% dextrose in distilled wateror saline and the active compound. Often it is useful to employ apharmaceutically and pharmacologically acceptable acid addition salt ofthe active compound that has appropriate solubility for the solventsemployed. Useful salts include the hydrochloride isothionate andmethanesulfonate salts. Useful formulations also comprise concentratedsolutions or solids comprising the active compound which on dilutionwith an appropriate solvent give a solution suitable for parenteraladministration.

The compounds of the present invention may be coupled to a class ofbiodegradable polymers useful in achieving controlled release of a drug,for example, polylactic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans,polycyanoacrylates and cross-linked or amphipathic block copolymers ofhydrogels.

The pharmaceutical composition and method of the present invention mayfurther comprise other therapeutically active compounds usually appliedin the treatment of the above mentioned conditions, including:osteoporosis, periodontal disease, bone fracture, bone damage followingbone reconstructive surgery, sarcopenia, frailty, aging skin, malehypogonadism, female sexual dysfunction, post-menopausal symptoms inwomen, atherosclerosis, hypercholesterolemia, hyperlipidemia, aplasticanemia and other hematopoietic disorders, pancreatic cancer, renalcancer, prostate cancer, arthritis and joint repair.

For the treatment and prevention of osteoporosis, the compounds of thepresent invention may be administered in combination with abone-strengthening agent selected from: resorption inhibitors,osteoanabolic agents, and other agents beneficial for the skeletonthrough the mechanisms which are not precisely defined, such as calciumsupplements, flavenoids and vitamin D analogues. For example, thecompounds of the instant invention may be effectively administered incombination with effective amounts of other agents such as estrogens,bisphosphonates, SERMs, cathepsin K inhibitors, osteoclast integrininhibitors, particularly α_(v)β₃ antagonists, vacuolar proton pumpinhibitors, VEGF, thiazolidinediones, calcitonin, protein kinaseinhibitos, parathyroid hormone and derivatives, calcium receptorantagonists, growth hormone secretagogues, growth hormone releasinghormone, insulin-like growth factor, bone morphogenic protein (BMP),inhibitors of BMP antagonism, prostaglandin derivatives, fibroblastgrowth factors, vitamin D and derivatives thereof, Vitamin K andderivatives thereof, soy isoflavones, calcium, and fluoride salts. Theconditions of periodontal disease, bone fracture, bone damage followingbone reconstructive surgery may also benefit from these combinedtreatments.

In the treatment of osteoporosis, the activity of the compounds of thepresent invention are distinct from that of the resorption inhibitors:estrogens, bisphosphonates, SERMs, calcitonin α_(v)β₃ antagonists andcathepsin K inhibitors, vacuolar proton pump inhibitors, agentsinterfering with the RANK/RANKL/Osteoprotegerin pathway, p38 inhibitorsor any other inhibitors of osteoclast generation or osteoclastactivation rather than inhibiting bone resorption, the compounds ofstructural formula I stimulate bone formation, acting preferentially oncortical bone, which is responsible for a significant part of bonestrength. The thickening of cortical bone substantially contributes to areduction in fracture risk, especially fractures of the hip. Thecombination of the tissue selective androgen receptor modulators ofstructural formula I with resorption inhibitors such as estrogen,bisphosphonates, antiestrogens, SERMs, calcitonin, osteoclast integrininhibitors HMG-CoA reductase inhibitors, proton pump inhibitors, andcathepsin K inhibitors is particularly useful because of thecomplementarity of the bone anabolic and antiresorptive actions.

Bone antiresportive agents are those agents which are known in the artto inhibit the resorption of bone and include, for example, estrogen andestrogen derivatives which include steroidal compounds having estrogenicactivity such as, for example, 17β-estradiol, estrone, conjugatedestrogen (PREMARIN®), equine estrogen, 17β-ethynyl estradiol, and thelike. The estrogen or estrogen derivative may be employed alone or incombination with a progestin or progestin derivative. Nonlimitingexamples of progestin derivatives are norethindrone andmedroxy-progesterone acetate.

Bisphosphonates are also bone anti-resorptive agents. Bisphosphonatecompounds may also be employed in combination with the compound ofstructural formula I of the present invention include:

-   4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid,-   N-methyl-4-amino-hydroxybutylidene-1,1-bisphosphonic acid,-   4-(N,N-dimethylamino-1-hydroxybutylidene-1,1-bisphosphonic acid,-   3-amino-1-hydroxypropyldene-1,1-bisphosphonic acid,-   3-(N,N-dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonic acid,-   1-hydroxy-3-(N-methyl-N-pentylamino)propylidene-1,1-bisphosphonic    acid,-   1-hydroxy-2-(3-pyridyl)ethylidene-1,1-bisphosphonic acid,-   4-(hydroxymethylene-1,1-bisphosphonic acid)piperidine,-   (1-hydroxyethylidene)-bisphosphonate,-   (dichloromethylene)-bisphosphonate,-   [1-hydroxy-2-imidazopyridin-(1,2-a)-3-ylethylidene]bisphosphonate,-   (6-amino-1-hydroxyethylidene)bisphosphonate,-   [1-hydroxy-2-(1H-imidazole-1-yl)ethylidene]bisphosphonate;    and their pharmaceutically acceptable salts. Especially preferred is    alendronate, 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid    monosodium salt, trihydrate. Methods for the preparation of    bisphosphonic acids may be found in, e.g., U.S. Pat. Nos. 3,251,907;    3,422,137; 3,584,125; 3,940,436; 3,944,599; 3,962,432; 4,054,598;    4,267,108; 4,327,039; 4,407,761; 4,578,376; 4,621,077; 4,624,947;    4,746,654; 4,761,406; 4,922,077. In particular, methods for the    preparation of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid    monosodium salt trihydrate may be found in U.S. Pat. Nos. 4,407,761    and 4,621,077.

Still further, antiestrogenic compounds such as raloxifene (see, e.g.,U.S. Pat. No. 5,393,763) clomiphene, zuclomiphene, enclomiphene,nafoxidene, CI-680, CI-628, CN-55,945-27, Mer-25, U-11, 555A, U-100A,and salts thereof, and the like (see, e.g., U.S. Pat. Nos. 4,729,999 and4,894,373) may be employed in combination with the compound ofstructural formula I in the methods and compositions of the presentinvention. These agents are also known as SERMs, or selective estrogenreceptor modulators, agents known in the art to prevent bone loss byinhibiting bone resorption via pathways believed to be similar to thoseof estrogens. These agents may beneficially be used in combination withthe compounds of the present invention to beneficially treat bonedisorders including osteoporosis. Such agents include, for example:tamoxifen, raloxifene, lasofoxifene, toremifene, azorxifene, EM-800,EM-652, TSE 424, clomiphene, droloxifene, idoxifene and levormeloxifene.(Goldstein, et al., A pharmacological review of selective oestrogenreceptor modulators. Human Reproduction Update, 6: 212–224, 2000, andLufkin, et al., The role of selective estrogen receptor modulators inthe prevention and treatment of Osteoporosis. Rheumatic Disease Clinicsof North America. 27 (1): 163–185, 2001.)

α_(v)β₃ antagonists suppress bone resorption and may be employed incombination with the tissue selective androgen receptor modulators ofstructural formula I for the treatment of bone disorders includingosteoporosis. Peptidyl as well as peptidomimetic antagonists of the αvβ3integrin receptor have been described both in the scientific and patentliterature. For example, reference is made to W. J. Hoekstra and B. L.Poulter, Curr. Med. Chem. 5: 195–204, 1998 and references cited therein;WO 95/32710; WO 95/37655; WO 97/01540; WO 97/37655; WO 98/08840; WO98/18460; WO 98/18461; WO 98/25892; WO 98/31359; WO 98/30542; WO99/15506; WO 99/15507; WO 00/03973; EP 853084; EP 854140; EP 854145;U.S. Pat. Nos. 5,204,350; 5,217,994; 5,639,754; 5,741,796; 5,780,426;5,929,120; 5,952,341; 6,017,925; and 6,048,861. Evidence of the abilityof αvβ3 integrin receptor antagonists to prevent bone resorption invitro and in vivo has been presented (V. W. Engleman, et al., “APeptidomimetic Antagonist of the αvβ3 Integrin Inhibits Bone ResorptionIn Vitro and Prevents Osteoporosis In Vivo,” J. Clin. Invest. 99:2284–2292, 1997; S. B. Rodan, et al., “A High Affinity Non-Peptide αvβ3Ligand Inhibits Osteoclast Activity In Vitro and In Vivo,” J. BoneMiner. Res. 11: S289, 1996; J. F. Gourvest, et al., “Prevention ofOVX-Induced Bone Loss With a Non-peptidic Ligand of the αvβ3 VitronectinReceptor,” Bone 23: S612, 1998; M. W. Lark, et al., “An Orally ActiveVitronectin Receptor αvβ3 Antagonist Prevents Bone Resorption In Vitroand In Vivo in the Ovariectomized Rat,” Bone 23: S219, 1998). Other αvβ3antagonists are described in R. M. Keenan, et al., “Discovery of PotentNonpeptide Vitronectin Receptor (αvβ3) Antagonists,” J. Med. Chem. 40:2289–2292, 1997; R. M. Keenan, et al., “Benzimidazole Derivatives AsArginine Mimetics in 1,4-Benzodiazepine Nonpeptide Vitronectin Receptor(αvβ3) Antagonists,” Bioorg. Med. Chem. Lett. 8: 3165–3170, 1998; and R.M. Keenan, et al., “Discovery of an Imidazopyridine-Containing1,4-Benzodiazepine Nonpeptide Vitronectin Receptor (αvβ3) AntagonistWith Efficacy in a Restenosis Model,” Bioorg. Med. Chem. Lett. 8:3171–3176, 1998. Still other benzazepine, benzodiazepine andbenzocycloheptene αvβ3 integrin receptor antagonists are described inthe following patent publications: WO 96/00574, WO 96/00730, WO96/06087, WO 96/26190, WO 97/24119, WO 97/24122, WO 97/24124, WO98/14192, WO 98/15278, WO 99/05107, WO 99/06049, WO 99/15170, WO99/15178, WO 99/15506, and U.S. Pat. No. 6,159,964, and WO 97/34865.αvβ3 integrin receptor antagonists having dibenzocycloheptene,dibenzocycloheptane and dibenzoxazepine scaffolds have been described inWO 97/01540, WO 98/30542, WO 99/11626, WO 99/15508, WO 00/33838, U.S.Pat. Nos. 6,008,213, and 6,069,158. Other osteoclast integrin receptorantagonists incorporating backbone conformational ring constraints havebeen described in the patent literature. Published patent applicationsor issued patents disclosing antagonists having a phenyl constraintinclude WO 98/00395, WO 99/32457, WO 99/37621, WO 99/44994, WO 99/45927,WO 99/52872, WO 99/52879, WO 99/52896, WO 00/06169, EP 0 820,988, EP 0820,991, U.S. Pat. Nos. 5,741,796; 5,773,644; 5,773,646; 5,843,906;5,852,210; 5,929,120; 5,952,381; 6,028,223; and 6,040,311. Publishedpatent applications or issued patents disclosing antagonists having amonocyclic ring constraint include WO 99/26945, WO 99/30709, WO99/30713, WO 99/31099, WO 99/59992, WO 00/00486, WO 00/09503, EP 0796,855, EP 0 928,790, EP 0 928,793, U.S. Pat. Nos. 5,710,159;5,723,480; 5,981,546; 6,017,926; and 6,066,648. Published patentapplications or issued patents disclosing antagonists having a bicyclicring constraint include WO 98/23608, WO 98/35949, WO 99/33798, EP 0853,084, U.S. Pat. Nos. 5,760,028; 5,919,792; and 5,925,655. Referenceis also made to the following reviews for additional scientific andpatent literature that concern alpha v integrin antagonists: M. E.Duggan, et al., “Ligands to the integrin receptor αvβ3, Exp. Opin. Ther.Patents, 10: 1367–1383, 2000; M. Gowen, et al., “Emerging therapies forosteoporosis,” Emerging Drugs, 5: 1–43, 2000; J. S. Kerr, et al., “Smallmolecule αv integrin antagonists: novel anticancer agents,” Exp. Opin.Invest. Drugs, 9: 1271–1291, 2000; and W. H. Miller, et al.,“Identification and in vivo efficacy of small-molecule antagonists ofintegrin αvβ3 (the vitronectin receptor),” Drug Discovery Today, 5:397–408, 2000.

Cathepsin K, formerly known as cathepsin O2, is a cysteine protease andis described in PCT International Application Publication No. WO96/13523, published May 9, 1996; U.S. Pat. No. 5,501,969, issued Mar. 3,1996; and U.S. Pat. No. 5,736,357, issued Apr. 7, 1998, all of which areincorporated by reference herein in their entirety. Cysteine proteases,specifically cathepsins, are linked to a number of disease conditions,such as tumor metastasis, inflammation, arthritis, and bone remodeling.At acidic pH's, cathepsins can degrade type-I collagen. Cathepsinprotease inhibitors can inhibit osteoclastic bone resorption byinhibiting the degradation of collagen fibers and are thus useful in thetreatment of bone resorption diseases, such as osteoporosis.

Members of the class of HMG-CoA reductase inhibitors, known as the“statins,” have been found to trigger the growth of new bone, replacingbone mass lost as a result of osteoporosis (The Wall Street Journal,Friday, Dec. 3, 1999, page B1). Therefore, the statins hold promise forthe treatment of bone resorption. Examples of HMG-CoA reductaseinhibitors include statins in their lactonized or dihydroxy open acidforms and pharmaceutically acceptable salts and esters thereof,including but not limited to lovastatin (see U.S. Pat. No. 4,342,767);simvastatin (see U.S. Pat. No. 4,444,784); dihydroxy open-acidsimvastatin, particularly the ammonium or calcium salts thereof;pravastatin, particularly the sodium salt thereof (see U.S. Pat. No.4,346,227); fluvastatin particularly the sodium salt thereof (see U.S.Pat. No. 5,354,772); atorvastatin, particularly the calcium salt thereof(see U.S. Pat. No. 5,273,995); cerivastatin, particularly the sodiumsalt thereof (see U.S. Pat. No. 5,177,080), rosuvastatin, also known asZD4522 (see U.S. Pat. No. 5,260,440) and pitavastatin also referred toas NK-104 or nisvastatin (see PCT international publication number WO97/23200).

Osteoclast vacuolar ATPase inhibitors, also called proton pumpinhibitors, may also be employed together with the tissue selectiveandrogen receptor modulator of structural formula I. The proton ATPasewhich is found on the apical membrane of the osteoclast has beenreported to play a significant role in the bone resorption process.Therefore, this proton pump represents an attractive target for thedesign of inhibitors of bone resorption which are potentially useful forthe treatment and prevention of osteoporosis and related metabolicdiseases (C. Farina, et al., “Selective inhibitors of the osteoclastvacuolar proton ATPase as novel bone resorption inhibitors,” DDT, 4:163–172, 1999).

The angiogenic factor VEGF has been shown to stimulate thebone-resorbing activity of isolated mature rabbit osteoclasts viabinding to its receptors on osteoclasts (M. Nakagawa, et al., “Vascularendothelial growth factor (VEGF) directly enhances osteoclastic boneresorption and survival of mature osteoclasts,” FEBS Letters, 473:161–164, 2000). Therefore, the development of antagonists of VEGFbinding to osteoclast receptors, such as KDR/Flk-1 and Flt-1, mayprovide yet a further approach to the treatment or prevention of boneresorption.

Activators of the peroxisome proliferator-activated receptor-γ (PPARγ),such as the thiazolidinediones (TZD's), inhibit osteoclast-like cellformation and bone resorption in vitro. Results reported by R. Okazaki,et al. in Endocrinolog, 140, pp 5060–5065, 1999 point to a localmechanism on bone marrow cells as well as a systemic one on glucosemetabolism. Nonlimiting examples of PPARγ activators includetroglitazone, pioglitazone, rosiglitazone, and BRL 49653.

Calcitonin may also be employed together with the tissue selectiveandrogen receptor modulator of structural formula I. Calcitonin ispreferentially administered as nasal spray. Azra, et al., Calcitonin,1996, In: J. P. Bilezikian, et al. Ed. Principles of Bone Biology, SanDiego: Academic Press; and Silverman. Calcitonin,. Rheumatic DiseaseClinics of North America 27:187–196, 2001).

Protein kinase inhibitors may also be employed together with the tissueselective androgen receptor modulator of structural formula L. Kinaseinhibitors include those disclosed in WO 0117562 and are in oneembodiment selected from inhibitors of P-38. Specific embodiments ofP-38 inhibitors useful in the present invention include: SB 203580(Badger, et al., Pharmacological profile of SB 203580, a selectiveinhibitor of cytokine suppressive binding protein/p38 kinase, in animalmodels of arthritis, bone resorption, endotoxin shock and immunefunction, J. Pharmacol. Exp. Ther. 279: 1453–1461, 1996).

Osteoanabolic agents are those agents that are known in the art to buildbone by increasing the production of the bone matrix. Such osteoanabolicagents include, for example, the various forms of parathyroid hormone(PTH) such as naturally occurring PTH(1–84), PTH (1–34), analogsthereof, native or with substitutions and particularly parathyroidhormone subcutaneous injection. PTH has been found to increase theactivity of osteoblasts, the cells that form bone, thereby promoting thesynthesis of new bone (Modem Drug Discovery, Vol. 3, No. 8, 2000). Instudies reported at the First World Congress on Osteoporosis held inChicago in June 2000, women in combined PTH-estrogen therapy exhibited a12.8% increase in spinal bone mass and a 4.4% increase in total hipmass. Another study presented at the same meeting showed that PTH couldincrease bone size as well as density. A clinical trial of the effect ofthe human parathyroid hormone 1–34 fragment [hPTH(1–34)] onpostmenopausal osteoporotic women resulted in ≧65% reduction in spinefractures and a 54% reduction in nonvertebral fractures, after a medianof 22 months of treatment (J. M. Hock, Bone, 27: 467–469, 2000 and S.Mohan, et al., Bone, 27: 471–478, 2000, and references cited therein).Thus, PTH and fragments thereof, such as hPTH(1–34), may prove to beefficacious in the treatment of osteoporosis alone or in combinationwith other agents, such as the tissue selective androgen receptormodulators of the present invention.

Also useful in combination with the SARMs of the present invention arecalcium receptor antagonists which induce the secretion of PTH asdescribed by Gowen, et al., in Antagonizing the parathyroid calciumreceptor stimulates parathyroid hormone secretion and bone formation inosteopenic rats, J Clin Invest. 105 :1595–604, 2000.

Growth hormone secretagogues, growth hormone, growth hormone releasinghormone and insulin-like growth factor and the like are alsoosteoanabolic agents which may be employed with the compounds accordingto structural formula I for the treatment of osteoporosis.Representative growth hormone secretagogues are disclosed in U.S. Pat.Nos. 3,239,345; 4,036,979; 4,411,890; 5,206,235; 5,283,241; 5,284,841;5,310,737; 5,317,017; 5,374,721; 5,430,144; 5,434,261; 5,438,136;5,494,919; 5,494,920; 5,492,916; 5,536,716; EPO Pat. Pub. No. 0,144,230;EPO Pat. Pub. No. 0,513,974; PCT Pat. Pub. No. WO 94/07486; PCT Pat.Pub. No. WO 94/08583; PCT Pat. Pub. No. WO 94/11012; PCT Pat. Pub. No.WO 94/13696; PCT Pat. Pub. No. WO 94/19367; PCT Pat. Pub. No. WO95/03289; PCT Pat. Pub. No. WO 95/03290; PCT Pat. Pub. No. WO 95/09633;PCT Pat. Pub. No. WO 95/11029; PCT Pat. Pub. No. WO 95/12598; PCT Pat.Pub. No. WO 95/13069; PCT Pat. Pub. No. WO 95/14666; PCT Pat. Pub. No.WO 95/16675; PCT Pat. Pub. No. WO 95/16692; PCT Pat. Pub. No. WO95/17422; PCT Pat. Pub. No. WO 95/17423; PCT Pat. Pub. No. WO 95/34311;PCT Pat. Pub. No. WO 96/02530; Science, 260, 1640–1643, Jun. 11, 1993;Ann. Rep. Med. Chem., 28, 177–186 (1993); Bioorg. Med. Chem. Ltrs.,4(22), 2709–2714, 1994; and Proc. Natl. Acad. Sci. USA 92, 7001–7005,July 1995.

Insulin-like growth factor (IGF) may also be employed together with thetissue selective androgen receptor modulator of structural formula I.Insulin-like growth factors may be selected from Insulin-like GrowthFactor I, alone or in combination with IGF binding protein 3 and IGF IL(Johannson and Rosen, The IGFs as potential therapy for metabolic bonediseases, 1996, In: Bilezikian, et. al. Ed. Principles of Bone Biology.San Diego: Academic Press; and Ghiron, et al., Effects of recombinantinsulin-like growth factor-I and growth hormone on bone turnover inelderly women, J Bone Miner Res. 10 :1844–52, 1995).

Bone morphogenic protein (BMP) may also be employed together with thetissue selective androgen receptor modulator of structural formula L.Bone morphogenic protein includes BMP 2, 3, 5, 6, 7, as well as relatedmolecules TGF beta and GDF 5. (Rosen, et al., Bone morphogeneticproteins. 1996. In: J. P. Bilezikian, et. al. Ed. Principles of BoneBiology, San Diego: Academic Press; and Wang EA, Bone morphogeneticproteins (BMPs): therapeutic potential in healing bony defects. TrendsBiotechnol. 11 :379–83, 1993)

Inhibitors of BMP antagonism may also be employed together with thetissue selective androgen receptor modulator of structural formula I.BMP antagonist inhibitors are in one embodiment selected from inhibitorsof the BMP antagonists SOST, noggin, chordin, gremlin, and dan (Massagueand Chen Controlling TGF-beta signaling, Genes Dev. 14 :627–44, 2000;Aspenberg, et al., The bone morphogenetic proteins antagonist Noggininhibits membranous ossification, J Bone Miner Res. 16: 497–500, 2001;Brunkow, et al., Bone dysplasia sclerosteosis results from loss of theSOST gene product, a novel cystine knot-containing protein, Am J HumGenet. 68: 577–89, 2001).

Prostaglandin derivatives may also be employed together with the tissueselective androgen receptor modulator of structural formula I.Prostaglandin derivatives are in one embodiment selected from agonistsof prostaglandin receptor EP1, EP2, EP4, FP and IP or a derivativethereof. Pilbeam, et al., Prostaglandins and bone metabolism, 1996, In:Bilezikian, et al. Ed. Principles of Bone Biology. San Diego: AcademicPress; Weinreb, et al., Expression of the prostaglandin E(2) (PGE(2))receptor subtype EP(4) and its regulation by PGE(2) in osteoblastic celllines and adult rat bone tissue(1), Bone. 28(3):275–81, 2001.

Fibroblast growth factors may also be employed together with the tissueselective androgen receptor modulator of structural formula I.Fibroblast growth factors include aFGF, bFGF and related peptides withFGF activity. Hurley Florkiewicz; Fibroblast growth factor and vascularendothelial growth factor families. 1996. In: J. P. Bilezikian, et. al.Ed. Principles of Bone Biology. San Diego: Academic Press.

In addition to bone resorption inhibitors and osteoanabolic agents,there are also other agents known to be beneficial for the skeletonthrough the mechanisms which are not precisely defined. These agents mayalso be favorably combined with the tissue selective androgen receptormodulator of structural formula I.

Vitamin D and Vitamin D derivatives may also be employed together withthe tissue selective androgen receptor modulator of structural formulaI. Vitamin D and Vitamin D derivatives include: natural vitamin D,25-OH-vitamin D3, 1α,25(OH)2 vitamin D3, 1α-OH-vitamin D3, 1α-OH-vitaminD2, dihydrotachysterol, 26,27-F6-1α,25(OH)2 vitamin D3,19-nor-1α,25(OH)2 vitamin D3, 22-oxacalcitriol, calcipotriol,1α,25(OH)2-16-ene-23-yne-vitamin D3 (Ro 23-7553), EB 1089,20-epi-1α,25(OH)2 vitamin D3, KH1060, ED71, 1α,24(S)-(OH)2 vitamin D3,1α,24(R)-(OH)2 vitamin D3. (Jones G. Pharmacological mechanisms oftherapeutics: vitamin D and analogs. 1996. In: J. P. Bilezikian, et. al.Ed. Principles of Bone Biology. San Diego: Academic Press).

Vitamin K and Vitamin K derivatives may also be employed together withthe tissue selective androgen receptor modulator of structural formulaI. Vitamin K and Vitamin K derivatives include: menatetrenone (vitaminK2). Shiraki, et al., Vitamin K2 (menatetrenone) effectively preventsfractures and sustains lumbar bone mineral density in osteoporosis, JBone Miner Res. 15: 515–21.

Soy isoflavones including ipriflavone may be employed together with thetissue selective androgen receptor modulator of structural formula I.

Fluoride salts, including sodium fluoride (NaF) or monosodiumfluorophosphate (MFP) may also be employed together with the tissueselective androgen receptor modulator of structural formula I Dietarycalcium supplements. may also be employed together with the tissueselective androgen receptor modulator of structural formula I. Dietarycalcium supplements include calcium carbonate, calcium citrate andnatural calcium salts (Heaney, Calcium, 1996, In: J. P. Bilezikian, et.al. Ed. Principles of Bone Biology. San Diego: Academic Press).

Daily dosage ranges for bone resorption inhibitors, osteoanabolic agentsand other agents which may be used to benefit the skeleton when used incombination with the compounds of structural formula I are those whichare known in the art. In such combinations, generally the daily dosagerange for the tissue selective androgen receptor modulator of structuralformula I is 0.01 to 1000 mg per adult human per day, more preferablyfrom 0.1 to 200 mg/day. However, adjustments to decrease the dose ofeach agent may be made due to the increased efficacy of the combinedagent.

In particular, when a bisphosphonate is employed, dosages of 2.5 to 100mg/day (measured as the free bisphosphonic acid) are appropriate fortreatment, more preferably 5 to 20 mg/day, especially about 10 mg/day.Prophylactically, doses of about 2.5 to about 10 mg/day and especiallyabout 5 mg/day should be employed. For reduction in side-effects, it maybe desirable to administer the combination of the compound of structuralformula I and the bisphosphonate once a week. For once weeklyadministration, doses of about 15 mg to 700 mg per week ofbisphosphonate and 0.07 to 7000 mg of the compound of structural formulaI may be employed, either separately, or in a combined dosage form. Thecompound of strucutral formula I may be favorably administered in acontrolled-release delivery device, particularly for once weeklyadministration.

For the treatment of atherosclerosis, hypercholesterolemia,hyperlipidemia, the compounds of structural formula I may be effectivelyadministered in combination with one or more additional active agents.The additional active agent or agents can be lipid altering compoundssuch as HMG-CoA reductase inhibitors, or agents having otherpharmaceutical activities, or agents that have both lipid-alteringeffects and other pharmaceutical activities. Examples of HMG-CoAreductase inhibitors include statins in their lactonized or dihydroxyopen acid forms and pharmaceutically acceptable salts and estersthereof, including but not limited to lovastatin (see U.S. Pat. No.4,342,767); simvastatin (see U.S. Pat. No. 4,444,784); dihydroxyopen-acid simvastatin, particularly the ammonium or calcium saltsthereof; pravastatin, particularly the sodium salt thereof (see U.S.Pat. No. 4,346,227); fluvastatin particularly the sodium salt thereof(see U.S. Pat. No. 5,354,772); atorvastatin, particularly the calciumsalt thereof (see U.S. Pat. No. 5,273,995); cerivastatin, particularlythe sodium salt thereof (see U.S. Pat. No. 5,177,080), and nisvastatinalso referred to as NK-104 (see PCT international publication number WO97/23200). Additional active agents which may be employed in combinationwith a compound of structural formula I include, but are not limited to,HMG-CoA synthase inhibitors; squalene epoxidase inhibitors; squalenesynthetase inhibitors (also known as squalene synthase inhibitors),acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitors includingselective inhibitors of ACAT-1 or ACAT-2 as well as dual inhibitors ofACAT1 and -2; microsomal triglyceride transfer protein (MTP) inhibitors;probucol; niacin; cholesterol absorption inhibitors such as SCH-58235also known as ezetimibe and1-(4-fluorophenyl)-3(R)-[3(S)-(4-fluorophenyl)-3-hydroxypropyl)]-4(S)-(4-hydroxyphenyl)-2-azetidinone,which is described in U.S. Pat. Nos. 5,767,115 and 5,846,966; bile acidsequestrants; LDL (low density lipoprotein) receptor inducers; plateletaggregation inhibitors, for example glycoprotein IIb/IIIa fibrinogenreceptor antagonists and aspirin; human peroxisome proliferatoractivated receptor gamma (PPARγ) agonists including the compoundscommonly referred to as glitazones for example troglitazone,pioglitazone and rosiglitazone and, including those compounds includedwithin the structural class known as thiazolidinediones as well as thosePPARγ agonists outside the thiazolidinedione structural class; PPARαagonists such as clofibrate, fenofibrate including micronizedfenofibrate, and gemfibrozil; PPAR dual α/γ agonists; vitamin B₆ (alsoknown as pyridoxine) and the pharmaceutically acceptable salts thereofsuch as the HCl salt; vitamin B₁₂ (also known as cyanocobalamin); folicacid or a pharmaceutically acceptable salt or ester thereof such as thesodium salt and the methylglucamine salt; anti-oxidant vitamins such asvitamin C and E and beta carotene; beta-blockers; angiotensin IIantagonists such as losartan; angiotensin converting enzyme inhibitorssuch as enalapril and captopril; calcium channel blockers such asnifedipine and diltiazam; endothelian antagonists; agents such as LXRligands that enhance ABC1 gene expression; bisphosphonate compounds suchas alendronate sodium; and cyclooxygenase-2 inhibitors such as rofecoxiband celecoxib as well as other agents known to be useful in thetreatment of these conditions.

Daily dosage ranges for HMG-CoA reductase inhibitors when used incombination with the compounds of structural formula I correspond tothose which are known in the art. Similarly, daily dosage ranges for theHMG-CoA synthase. inhibitors; squalene epoxidase inhibitors; squalenesynthetase inhibitors (also known as squalene synthase inhibitors),acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitors includingselective inhibitors of ACAT-1 or ACAT-2 as well as dual inhibitors ofACAT1 and -2; microsomal triglyceride transfer protein (MTP) inhibitors;probucol; niacin; cholesterol absorption inhibitors including ezetimibe;bile acid sequestrants; LDL (low density lipoprotein) receptor inducers;platelet aggregation inhibitors, including glycoprotein IIb/IIIafibrinogen receptor antagonists and aspirin; human peroxisomeproliferator activated receptor gamma (PPARγ) agonists; PPARαagonists;PPAR dual α/γ agonists; vitamin B₆; vitamin B₁₂; folic acid;anti-oxidant vitamins; beta-blockers; angiotensin II antagonists;angiotensin converting enzyme inhibitors; calcium channel blockers;endothelian antagonists; agents such as LXR ligands that enhance ABC1gene expression; bisphosphonate compounds; and cyclooxygenase-2inhibitors also corespond to those which are known in the art, althoughdue to the combined action with the compounds of structural formula I,the dosage may be somewhat lower when administered in combination.

For the treatment of male and/or female sexual dysfunction, the SARMcompounds of the present invention may be administered together withagents useful in the treatment of male and/or female sexual dysfunction,such as type V cyclic-GMP-specific phosphodiesterase (PDE-V) inhibitors,including sildenafil and IC-351; alpha-adrenergic receptor antagonists,including phentolamine and yohimbine and pharmaceutically acceptablesalts thereof; and dopamine receptor agonists, such as apomorphine.

In one embodiment of a combination for the treatment of male or femalesexual dysfunction, the second ingredient to be combined with a SARMcompound can be a type V cyclic-GUT-specific phosphodiesterase (PDE-V)inhibitor, such as sildenafil and IC-351 or a pharmaceuticallyacceptable salt thereof; an alpha-adrenergic receptor antagonist, suchas phentolamine and yohimbine or a pharmaceutically acceptable saltthereof; or a dopamine receptor agonist, such as apomorphine or apharmaceutically acceptable salt thereof.

In accordance with the method of the present invention, the individualcomponents of the combination can be administered separately atdifferent times during the course of therapy or concurrently in dividedor single combination forms. The instant invention is therefore to beunderstood as embracing all such regimes of simultaneous or alternatingtreatment and the term “administering” is to be interpreted accordingly.It will be understood that the scope of combinations of the compounds ofthis invention with other agents useful for treating diseases caused byandrogen deficiency or that can be ameliorated by addition of androgen.

Compounds according to the present invention may be prepared accordingto the procedures outlined in Scheme A and as detailed in the Examples.

The following examples are provided to further illustrate details forthe preparation and use of the compounds of the present invention. Theexamples are not intended to be limitations on the scope of the instantinvention in any way, and they should not be so construed. Furthermore,the compounds described in the following examples are not to beconstrued as forming the only genus that is considered as the invention,and any combination of the compounds or their moieties may itself form agenus. Those skilled in the art will readily understand that knownvariations of the conditions and processes of the following preparativeprocedures can be used to prepare these compounds. All temperatures arein degrees Celsius unless noted otherwise.

Abbreviations: Ac represents acetyl; AR is the androgen receptor; aq isaqueous; cPr is cyclopropyl; ddWater is distilled, deionized water; DEAis N,N-diethylaniline; DIBAL is diisobutylaluminum hydride; DMEM isDulbecco's Modified Eagle Media; DMF is dimethyl formamide; EDTA isethylenediaminetetraacetic acid; EGTA is ethylenebis(oxyethylenenitrolo) tetraacetic acid; Et represents ethyl; FCS isfetal calf serum; HAP is hydroxylapatite; hAR is the human androgenreceptor; Me is methyl; MEM is Minimum Essential Media; min. is minute;NMM is N-methyl morpholine; NMR is nuclear magnetic resonance; PBS isphosphate buffered saline (8 g NaCl, 0.2 g KCl, 1.44 g Na₂HPO₄, 0.24KH₂PO₄ dissolve into H₂O to make 1 L and adjust pH to 7.4 with HCl); Phis phenyl; pQCT is peripheral quantitative computer tomography; R1881 ismethyltrienolone, an androgen receptor agonist; RhAR is the rhesusandrogen receptor; rt is room temperature; SARM is a tissue selectiveandrogen receptor modulator; SEAP is secreted alkaline phosphatase; TACis triamcinolone acetonide; tBu is tertiary butyl; THF istetrahydrofuran.

EXAMPLE 14-(Trifluoromethyl)-7,8,9,10-tetrahydrochromeno[7,6-b]azepin-2(6H)-one(1-5)

-   Step 1: 7-Methoxy-3,4-dihydronaphthalen-1(2H)-one oxime (1-2)

To a solution of 7-methoxy-1-tetralone 1-1 (7.0 g, 40 mmol) in EtOH (150mL) were added hydroxylamine hydrochloride (5.52 g, 80 mmol), andAMBERLYST A-21 ion-exchange resin (8.5 g). The mixture was stirred for24 h. The resin was removed by filtration and the filtrate concentrated.The residue was diluted with diethyl ether and washed with brine. Theorganic solution was dried over MgSO₄, filtered and concentrated to givethe desired product. Data for 1-2: ¹HNMR (500 MHz, CD₃OD) δ 7.43 (d,J=2.7 Hz, 1H), 7.08 (d, J=8.5 Hz, 1H), 6.88 (dd, J=8.5, 2.7 Hz, 1H),3.78 (s, 3H), 2.78 (m, 2H), 2.69 (m, 2H), 1.83 (m, 2H) ppm.

-   Step 2: 8-Methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine (1-3)

A cooled (0° C.) solution of oxime 1-2 (0.78 g, 4.0 mmol) in THF (100mL) was treated with DIBAL (20.0 mmol, 1M in 1HF) via dropwise addition.The reaction was warmed to rt. After stirring for 4 d, the reaction wasquenched with EtOAc and partitioned between 1N aq NaOH and EtOAc. Theorganic layer was washed with brine, dried over K₂CO₃, filtered andconcentrated. The residue was absorbed onto silica gel then purified onan ISCO automated system affixed with a BIOTAGE flash 40(s) cartridgeeluting with 5–20% EtOAc in hexane. Data for 1-3: ¹HNMR (500 MHz, CDCl₃)δ 7.03 (m, 1H), 6.42 (m, 1H), 6.33 (m, 1H), 3.78 (s, 3H), 3.08 (m, 2H),2.75 (m, 2H), 1.82 (m, 2H), 1.65 (m, 2H) ppm.

-   Step 3: 8-Hydroxy-2,3,4,5-tetrahydro-1H-1-benzazepine (1-4)

Methyl ether 1-3 (0.22 g, 1.2 mmol) was treated with neat HBr (5 mL) andthe solution heated to reflux for 2 h. The reaction was neutralized topH 9 with aq NH₄OH and the product was extracted with EtOAc. The organiclayer was washed with brine, dried over K₂CO₃, filtered, andconcentrated. The residual brown oil was absorbed on silica gel thenpurified on an ISCO automated system affixed with a BIOTAGE flash 40(S)cartridge eluting with 5–15% EtOAc in hexane over 45 min at 20 mL/min.Data for 1-4: ¹HNMR (500 MHz, DMSO-d6) δ 8.81 (s, 1H), 6.75 (d, J=8.1Hz, 1H), 6.22 (d, J=2.4 Hz, 1H), 6.08 (dd, J=8.1, 2.4 Hz, 1H), 2.87 (m,2H), 2.51 (m, 2H), 1.63 (m, 2H), 1.50 (m, 2H) ppm.

-   Step 4:    4-(Trifluoromethyl)-7,8,9,10-tetrahydrochromeno[7,6-b]azepin-2(6H)-one    (1-5)

Equimolar amounts of 8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine 1-4(0.18 g, 1.12 mmol), ethyl 4,4,4-trifluoroacetoacetate (0.205 g, 1.12mmol), and zinc chloride (1.12 mL, 1M solution in Et₂O) were combined ina pressure bottle with 10 mL absolute EtOH. The bottle was sealed andallowed to stir at 100° C. for overnight. The reaction darkened from aclear and colorless solution to a dark green solution. After cooling tort, the reaction solution was absorbed onto silica gel and purified onan ISCO automated system affixed with a BIOTAGE flash 40(S) cartridgeeluting 5–25% EtOAc in hexane to provide the desired product 1-5. Datafor 1-5: HRMS Calcd (M+1) 284.0893; found 284.0901.

EXAMPLE 24-(Trifluoromethyl)-1,6,7,8,9,10-hexahydro-2H-azepino[3,2-g]quinolin-2-one(2-5)

-   Step 1: 2,3,4,5-Tetrahydro-1H-1-benzazepin-8-amine (2-4)

To a solution of 7-nitro-1-tetralone 2-1 (5.0 g, 26 mmol) in 100 mLethanol was added tin (II) chloride (14.9 g, 78.5 mmol). The mixturechanged from colorless to a deep red. The reaction was heated to refluxand allowed to stir for 2 h under N₂. The reaction was cooled, andconcentrated in vacuo. The remaining residue was dissolved in EtOAc andwashed with 1N NaOH which generated a thick white precipitate. Theorganic layer was washed with water (2×200 mL), and brine. The organicsolution was dried over K₂CO₃, filtered and concentrated to yield 1.2 gof the amino-tetralone 2-2. A solution of tetralone 2-2 (1.2 g, 7.44mmol) in EtOH (150 mL) was treated with hydroxylamine hydrochloride(14.9 mmol), and AMBERLYST A-21 ion-exchange resin (5 g). The mixturewas allowed to stir until starting material was completely consumed (24h). The resin was removed by filtration and the filtrate concentrated invacuo. The residual oil was partitioned between water and diethyl ether.The organic layer was washed with brine, dried over MgSO₄, filtered andconcentrated to give the desired product 2-3. A ice-cooled solution ofoxime 2-3 (1 g, 5.7 mmol) in benzene (100 mL) was treated with DIBAL (40mL, 1M in dichloromethane). The reaction was gradually warmed to rt thenstirred for 2 days at ambient temperature. The reaction was quenchedwith EtOAc and partitioned between 1N aqueous NaOH and EtOAc. Theorganic layer was washed with brine, dried over K₂CO₃, filtered andconcentrated. The remaining oil was absorbed onto silica gel thenpurified on an ISCO automated system affixed with a BIOTAGE flash 40(s)cartridge eluted 5–50% EtOAc in hexane over 1.5 h. Data for 2-4: ¹HNMR(500 MHz, CDCl₃) δ 6.87 (d, J=7.8 Hz, 1H), 6.18 (dd, J=7.8, 2.2 Hz, 1H),6.08 (d, J=2.2 Hz, 1H), 3.01 (m, 2H), 2.65 (m, 2H), 1.75 (m, 2H), 1.58(m, 2H) ppm.

-   Step 2:    4-(Trifluoromethyl)-1,6,7,8,9,10-hexahydro-2H-azepino[3,2-g]quinolin-2-one    (2-5)

Equimolar amounts of benzazepine 2-4 (0.2 g, 1.3 mmol), ethyl4,4,4-trifluoroacetoacetate (0.19 mL), and zinc chloride (1.3 mL of 1Msolution in Et₂O) were combined in a pressure bottle with 1 mL absoluteEtOH. The bottle was sealed and heated at 100° C. for overnight. Thereaction changed from light brown to a dark orange. The reaction wascooled and then absorbed onto silica gel and purified on an ISCOautomated system affixed with a BIOTAGE flash 40(S) cartridge eluted5–45% EtOAc in hexane over 55 min. Data for 2-5: ¹HNMR (500 MHz, CDCl₃)δ 7.50 (m, 1H), 6.84 (m, 1H), 6.65 (m, 1H), 3.22 (m, 2H), 2.86 (m, 2H),1.85 (m, 2H), 1.78 (m, 2H) ppm.

EXAMPLE 3 1,6,7,8,9,10-Hexahydro-2H-azepino[3,2-g]quinolin-2-one (3-1)

A solution of 2,3,4,5-tetrahydro-1H-1-benzazapin-8-amine (0.6 g, 3.4mmol) and 3-ethoxyacryloyl chloride (0.45 g, 3.4 mmol) in CH₂Cl₂ (50 mL)and 3N NaOH (10 mL) was stirred for 1 h at ambient temperature. Thereaction was partitioned between CH₂Cl₂ and water. The organic layer wasconcentrated and the remaining brown oil was dissolved in 70% aq. H₂SO₄(20 mL) and heated gently (50° C.) for 2 h. The reaction was cooled andneutralized with aq. NH₄OH and partitioned between water and EtOAc. Theorganic layer was washed with brine, dried over MgSO₄, filtered andconcentrated. The residue was dissolved in DMF (1 mL) and purified on aGILSON automated system affixed with a YMC COMBIFLASH 50 mm×20 mmreverse phase column eluted 5–95% CH₃CN in water at 30 mL/min over 10.5min to provide pure desired product. HRMS m/z (M+1) calcd 215.1179;found 215.1186.

EXAMPLE 48-(R)-Methyl-4-(trifluoromethyl)-7,8,9,10-tetrahydrochromeno[7,6-b]azepin-2(6H)-oneand8-(S)-Methyl-4-(trifluoromethyl)-7,8,9,10-tetrahydrochromeno[7,6-b]azepin-2(6H)-one(4-5)

-   Step 1: 7-Methoxy-2(R,S)-methyl-3,4-dihydronaphthalen-1(2H)-one    (4-1) and 7-Methoxy-2,2-dimethyl-3,4-dihydronaphthalen-1(2H)-one    (4-2)

A solution of lithium bis(trimethylsilyl)amide (17 mL of a 1M solution)in THF (30 mL) was cooled in a dry ice-acetone bath. A solution of7-methoxy-1-tetralone (3.0 g, 17.0 mmol) in THF (5 mL) was addeddropwise, and the solution was allowed to warm to 0° C. by utilizing anice bath. After stirring for 10 min, iodomethane (2.41 g, 17.0 mmol, 1.1mL) was added and the reaction was warmed to rt and allowed to stir for16 h. The reaction was quenched with water and extracted with EtOAc. Theorganic layer was washed with brine, dried over MgSO₄, filtered, andconcentrated. Analysis by HPLC-MS showed starting material and two newproducts consistent with mono- and dialkylation. The residue wasabsorbed onto silica gel and purified on an ISCO automated systemaffixed with a BIOTAGE Flash 40(M) cartridge eluting with 5–10% EtOAc inhexane at 40 mL/min over 1 h to yield the monoalkylated adduct 4-1 (MSm/z (M+1) 190) and 2,2-dimethyl adduct 4-2 (MS m/z (M+1) 204).

-   Step 2: 7-Methoxy-2-(R,S)-methyl-3,4-dihydronaphthalen-1(2H)-one    oxime (4-3)

A solution of 7-methoxy-2-(R,S)-methyl-3,4-dihydronaphthalen-1(2H)-one4-1 (0.85 g, 4.5 mmol) and hydroxylamine hydrochloride (0.6 g, 8.9 mmol)in EtOH (15 mL) was treated with AMBERLYST A-21 ion-exchange resin (5.0g). The mixture was heated to reflux and allowed to stir until startingmaterial was fully consumed (24 h). The reaction was cooled and theresin was removed by filtration. After concentration, the remaining oilwas partitioned between water and diethyl ether. The organic layer waswashed with brine, dried over MgSO₄, filtered and concentrated to givethe desired product 4-3. HPLC-MS (MS m/z (M+1) 205).

-   Step 3: 3-(R,S)-Methyl-2,3,4,5-tetrahydro-1H-1-benzazepin-8-ol (4-4)

To a solution of 7-methoxy-2-methyl-3,4-dihydronaphthalen-1(2H)-oneoxime 4-3 (1.1 g, 5.4 mmol) in benzene (20 mL) under N₂ was added DIBAL(27 mL of a 1M in heptane, 27 mmol). The reaction was heated at refluxfor 16 h. The reaction was quenched with saturated sodium potassiumtartrate (Rochelle's salt) and partitioned between water and EtOAc. Theorganic layer was washed with brine, dried over MgSO₄, filtered andconcentrated. The remaining oil was absorbed onto silica gel thenpurified on an ISCO automated system affixed with a BIOTAGE flash 40(s)cartridge eluted 5–50% EtOAc in hexane over 1.5 h at 20 mL/min to affordthe desired product 4–4. HPLC/MS (MS m/z (M+1) 177).

-   Step 4:    8-(R)-Methyl-4-(trifluoromethyl)-7,8,9,10-tetrahydrochromeno[7,6-b]azepin-2(6H)-one    and    8-(S)-Methyl-4-(trifluoromethyl)-7,8,9,10-tetrahydrochromeno[7,6-b]azepin-2(6H)-one    (4-5)

Equimolar amounts of 3-methyl-2,3,4,5-tetrahydro-1H-1-benzazepin-8-ol(0.1 g, 1.57 mmol), ethyl 2,2,2-trifluoroacetoacetate (0.08 mL), andzinc chloride (0.6 mL of 1M solution in Et₂O) in absolute EtOH (1 mL)were combined in a pressure bottle. The bottle was sealed and heated at100° C. for 16 h. After cooling to rt, the reaction mixture was absorbedonto silica gel and then purified on an ISCO automated system affixedwith a BIOTAGE Flash 40(s) cartridge eluting with 5–20% EtOAc in hexaneat 20 mL/min for 45 min to provide the desired product racemate: HRMSm/z (M+1) calcd 298.1049; found 298.1052. The racemic product wasresolved to yield pure enantiomers on a CHIRALIAK AD column (250 mm×4.6mm eluting with 95% hexane plus 0.1% DEA 5% EtOH at 1 mL/min). The firstenantiomer eluted 4-5a at 12.2 min ([α]=negative) and the secondenantiomer 4-5b eluted at 13.4 min ([α]=positive).

EXAMPLE 58-Spirocyclopropyl-4-(trifluoromethyl)-7,8,9,10-tetrahydrochromeno[7,6-b]azepin-2(6H)-one(5-4)

-   Step 1: (2-Chloroethyl)(dimethyl)sulfonium iodide

A 150 mL pressure tube was charged with 2-chloroethyl methyl sulfide(5.0 g, 45 mmol), acetonitrile (30 mL), and iodomethane (2.8 mL). Thetube was sealed and allowed to stir at room temperature for 3 days overwhich time a large amount of precipitate formed. The precipitate wascollected by filtration, washed with acetonitrile, and dried under highvacuum. ¹HNMR data (500 MHz, DMSO-d6) d 4.17–4.12 (t, 1H); 3.85–3.75 (m,2H); 3.59–3.54 (t, 1H), 2.98 (s, 3H); 2.93 (s, 3H) ppm.

-   Step 2: 7-Methoxy-2-spirocyclopropyl-3,4-dihydronaphthalen-1(2H)-one    (5-1)

To a solution of 7-methoxy-1-tetralone (2.75 g, 15 mmol) in t-BuOH (25mL) under N₂ was added sodium iodide (0.5 g) and NaH (0.7 g, 60%dispersion in mineral oil washed 3× with hexane then suspended int-BuOH). After stirring for 15 min, (2-chloroethyl)dimethylsulfoniumiodide (4.0 g, 15 mmol) was added and the reaction stirred at rtovernight. The reaction was quenched with water and extracted withEtOAc. The organic layer was washed with brine, dried over MgSO₄,filtered, then concentrated. The remaining clear oil was absorbed ontosilica gel and purified on an ISCO automated system affixed with aBIOTAGE flash 40(L) cartridge eluted 5–15% EtOAc in hexane over 1 h at40 mL/min to give the desired product 5-1. MS m/z (M+1) 202.

-   Step 3: 7-Methoxy-2-spirocyclopropyl-3,4-dihydronaphthalen-1(2H)-one    oxime (5-2)

This compound was produced by the same method as in Scheme 4 with thesubstitution of7-methoxy-2-spirocyclopropyl-3,4-dihydronaphthalen-1(2H)-one 5-1 for7-methoxy-2-(R,S)-methyl-3,4-dihydronaphthalen-1(2H)-one 4-1. MS m/z(M+1) 217.

-   Step 4: 3-Spirocyclopropyl-2,3,4,5-tetrahydro-1H-1-benzazepin-8-ol    (5-3)

This compound was prepared by the same method as in Scheme 4 with thesubstitution of7-methoxy-2-spirocyclopropyl-3,4-dihydronaphthalen-1(2H)-one oxime 5-2for 7-methoxy-2-(R,S)-methyl-3,4-dihydronaphthalen-1(2H)-one oxime 4-3.MS m/z (M+1) 189.

-   Step 5:    8-Spirocyclopropyl-4-(trifluoromethyl)-7,8,9,10-tetrahydrochromeno[7,6-b]azepin-2(6H)-one    (5-4)

This compound was prepared by the same method as in Scheme 4 with thesubstitution of3-spirocyclopropyl-2,3,4,5-tetrahydro-1H-1-benzazepin-8-ol 5-3 for3-methyl-2,3,4,5-tetrahydro-1H-1-benzazepin-8-ol 4-4. HRMS m/z (M+1)calcd 310.1050; found 310.1059.

Table 1

The following compounds were prepared by the methods illustrated inScheme 4.

Compound HRMS (Example) Name m/z (M + 1)

8-(R,S)-Propyl-4-(trifluoromethyl)-7,8,9,10-tetrahydrochromeno[7,6-b]azepin-2(6H)-oneCalcd.326.1363Found326.1369

8-Dimethyl-4-(trifluoromethy1)-7,8,9,10-tetrahydrochromeno[7,6-b]azepin-2(6H)-oneCalcd.312.1206Found312.1213

8-(R,S)-Benzyl-4-(trifluoromethyl)-7,8,9,10-tetrahydrochromeno[7,6-b]azepin-2(6H)-oneCalcd.374.1363Found374.1353

8-(R,S)-Ethyl-4-(trifluoromethyl)-7,8,9,10-tetrahydrochromeno[7,6-b]azepin-2(6H)-oneCalcd.312.1206Found312.1216

8-(R,S)-Cyclopropylmethyl-4-(trifluoromethyl)-7,8,9,10-tetrahydrochromeno[7,6-b]azepin-2(6H)-oneCalcd.338.1363Found338.1383

EXAMPLE 114,8-(R,S)-Dimethyl-7,8,9,10-tetrahydrochromeno[7,6-b]azepin-2(6H)-one(6-1)

This compound was prepared by the same method as Example 4 with thesubstitution of ethyl acetoacetate for ethyl2,2,2-trifluoromethylacetoacetate. HRMS m/z (M+1) calcd. 244.1332, found244.1329.

EXAMPLE 124-Methyl-8-(R,S)-propyl-7,8,9,10-tetrahydrochromeno[7,6-b]azepin-2(6H)-one(7-2)

This compound was prepared by the same method as in Scheme 4 with thesubstitution of ethyl acetoacetate for ethyl2,2,2-trifluoromethylacetoacetate. HRMS m/z (M+1) calcd. 272.1645, found272.1645.

EXAMPLE 13

Oral Composition

As a specific embodiment of an oral composition of a compound of thisinvention, 50 mg of a compound of the present invention is formattedwith sufficient finely divided lactose to provide a total amount of 580to 590 mg to fill a size 0 hard gelatin capsule.

EXAMPLE 14

Transdermal Patch Formulation

Ingredient Amount Compound of formula I  40 g Silicone fluid  45 gColloidal silicone dioxide 2.5 gThe silicone fluid and compound of structural formula I are mixedtogether and the colloidal silicone dioxide is added to increaseviscosity. The material is then dosed into a subsequently heat sealedpolymeric laminate comprised of the following: polyester release liner,skin contact adhesive composed of silicone or acrylic polymers, acontrol membrane which is a polyolefin (e.g. polyethylene, polyvinylacetate or polyurethane), and an impermeable backing membrane made of apolyester multilaminate. The resulting laminated sheet is then cut into10 cm² patches. For 100 Patches.

EXAMPLE 15

Suppository

Ingredient Amount Compound of structural formula I  25 g Polyethyleneglycol 1000 1481 g Polyethylene glycol 4000  494 gThe polyethylene glycol 1000 and polyethylene glycol 4000 are mixed andmelted. The compound of structural formula I is mixed into the moltenmixture, poured into molds and allowed to cool. For 1000 suppositories.

EXAMPLE 16

Injectable Solution

Ingredient Amount compound of structural formula I  5 g Buffering agentsq.s. Propylene glycol 400 mg Water for injection 600 mLThe compound of structural formula I and buffering agents are dissolvedin the propylene glycol at about 50° C. The water for injection is thenadded with stirring and the resulting solution is filtered, filled intoampules, sealed and sterilized by autoclaving. For 1000 Ampules.

EXAMPLE 17

Injectable Solution

Ingredient Amount Compound of structural formula I  5 g Buffering agentsq.s. Magnesium sulfate heptahydrate 100 mg Water for injection 880 mLThe compound of structural formula I, magnesium sulfate heptahydrate andbuffering agents are dissolved in the water for injection with stirring,and the resulting solution is filtered, filled into ampules, sealed andsterilized by autoclaving. For 1000 Ampules.

Following are assays to characterize the activity of the tissueselective androgen receptor modulators of the present invention.

In Vitro and In Vivo Assays for Identification of Compounds with SARMActivity

Hydroxylapatite-based Radioligand Displacement Assay of CompoundAffinity for Endogenously Expressed AR

Materials:

-   Binding Buffer. TEGM (10 mM Tris-HCl, 1 mM EDTA, 10% glycerol, 1 mM    beta-mecaptoethanol, 10 mM Sodium Molybdate, pH 7.2)-   50% HAP Slurry: Calbiochem Hydroxylapatite, Fast Flow, in 10 mM    Tris, pH 8.0 and 1 mM EDTA.-   Wash Buffer: 40 mM Tris, pH7.5, 100 mM KCl, 1 mM EDTA and 1 mM EGTA.    95% EtOH-   Methyltrienolone, [17a-methyl-³H], (R1881*); NEN NET590-   Methyltrienolone (R1881), NEN NLP005 (dissolve in 95% EtOH)-   Dihydrotestosterone (DHT) [1,2,4,5,6,7-³H(N)] NEN NET453-   Hydroxylapatite Fast Flow; Calbiochem Cat#391947-   Molybdate=Molybdic Acid (Sigma, M1651)    MDA-MB453 Cell Culture Media:

RPMI 1640 (Gibco 11835–055) w/23.8 mM NaHCO₃, 2mM L-glutamine In 500 mLof complete media Final conc.  10 mL (1 M Hepes) 20 mM   5 mL (200 mML-glu)  4 mM 0.5 mL (10 mg/mL human insulin) 10 μg/mL in 0.01 N HClCalbiochem#407694-S)  50 mL FBS (Sigma F2442) 10%   1 mL (10 mg/mLGentamicin 20 μg/mL Gibco#15710-072)Cell Passaging:

Cells (Hall R. E., et al., European Journal of Cancer, Vol. 30A (4),484–490 (1994) are rinsed twice in PBS, phenol red free Trypsin-EDTA isdiluted in the same PBS 1:10. The cell layers are rinsed with 1×Trypsin, extra Trypsin is poured out, and the cell layers are incubatedat 37° C. for ˜2 min. The flask is tapped and checked to for signs ofcell detachment. Once the cells are starting to sliding off the flask,the complete media is added to kill the trypsin. The cells are countedat this point, then diluted to the appropriate concentration and splitinto flasks or dishes for further culturing (Usually 1:3 to 1:6dilution).

Preparation of MDA-MB453 Cell Lysate

When the MDA cells are 70 to 85% confluent, they are detached asdescribed above, and collected by centrifuging at 1000 g for 10 min at4° C. The cell pellet is washed 2× with TEGM (10 mM Tris-HCl, 1 mM EDTA,10% glycerol, 1 mM beta-mercaptoethanol, 10 mM Sodium Molybdate, pH7.2). After the final wash, the cells are resuspended in TEGM at aconcentration of 10⁷ cells/mL. The cell suspension is snap frozen inliquid N₂ or ethanol dry ice bath and transferred to −80° C. freezer ondry ice. Before setting up the binding assay, the frozen samples areleft on ice-water to just thaw (˜1 hr). Then the samples are centrifugedat 12,500 g to 20,000 g for 30 min at 4° C. The supernatant is used toset-up assay right away. If using 50 μL of supernatant, the testcompound can be prepared in 50 μL of the TEGM buffer.

Procedure for Multiple Compound Screening:

1× TEGM buffer is prepared, and the isotope-containing assay mixture isprepared in the following order: EtOH (2% final Conc. in reaction),³H-R1881 or ³H-DHT (0.5 nM final Conc. in reaction) and 1× TEGM. [eg.For 100 samples, 200 μL (100×2) of EtOH+4.25 μL of 1:10 ³H-R1881stock+2300 μL (100×23) 1× TEGM]. The compound is serially diluted, e.g.,if starting final conc. is 1 μM, and the compound is in 25 μL ofsolution, for duplicate samples, 75 μL of 4×1 μM solution is made and 3μL of 100 μM is added to 72 μL of buffer, and 1:5 serial dilution.

25 μL of ³H-R1881 trace and 25 μL compound solution are first mixedtogether, followed by addition of 50 μL receptor solution. The reactionis gently mixed, spun briefly at about 200 rpm and incubated at 4° C.overnight. 100 μL of 50% HAP slurry is prepared and 100 μL of 50% HAPslurry is added to the incubated reaction which is then vortexed andincubated on ice for 5 to 10 minutes. The reaction mixture is vortexedtwice more to resuspend HAP while incubating reaction. The samples in96-well format are then washed in wash buffer using The FilterMate™Universal Harvester plate washer (Packard). The washing processtransfers HAP pellet containing ligand-bound expressed receptor toUnifilter-96 GF/B filter plate (Packard). The HAP pellet on the filterplate is incubated with 50 μL of MICROSCINT (Packard) scintillint for ½hour before being counted on the TopCount micro scintillation counter(Packard). IC₅₀s are calculated using R1881 as a reference. Tissueselective androgen receptor modulators of the present inventiontypically have IC₅₀ values of 1 micromolar or less.

MMP1 Promoter Suppression, Transient Transfection Assay (TRAMPS)

HepG2 cells are cultured in phenol red free MEM containing 10%charcoal-treated FCS at 37C with 5% CO₂. For transfection, cells areplated at 10,000 cells/well in 96 well white, clear bottom plates.Twenty four hours later, cells are co-transfected with a MMP1promoter-luciferase reporter construct and a rhesus monkey expressionconstruct (50:1 ratio) using FuGENE6 transfection reagent, following theprotocol recommended by manufacture. The MMP1 promoter-luciferasereporter construct is generated by insertion of a human MMP1 promoterfragment (−179/+63) into pGL2 luciferase reporter construct (Promega)and a rhesus monkey AR expression construct is generated in a CMV-Tag2Bexpression vector (Stratagene). Cells are further cultured for 24 hoursand then treated with ligands in the presence of 100 nMphorbol-12-myristate-13-acetate (PMA), used to increase the basalactivity of MMP1 promoter. The ligands are added at this point, at arange of 1000 nM to 0.03 nM, 10 dilutions, at a concentration on 10×,1/10th volume. (example: 10 microliters of ligand at 10× added to 100microliters of media already in the well.) Cells are further culturedfor additional 48 hours. Cells are then washed twice with PBS and lysedby adding 70 μL of Lysis Buffer (1×, Promega) to the wells. Theluciferase activity is measured in a 96 well format using a 1450Microbeta Jet (Perkin Elmer) luminometer. AR agonism of tissue selectiveandrogen receptor modulators is presented as suppression of luciferasesignal from the PMA-stimulated control levels EC₅₀ and Emax values arereported. Tissue selective androgen receptor modulators of the presentinvention typically agonize repression typically with submicromolar EC₅₀values and Emax values greater than about 50%.

REFERENCES

-   1. Newberry E P, Willis D, Latifi T, Boudreaux J M, Towler D A.    Fibroblast growth factor receptor signaling activates the human    interstitial collagenase promoter via the bipartite Ets-AP1 element.    Mol Endocrinol. 1997 July; 11(8): 1129–44.-   2. Schneikert J, Peterziel H, Defossez P A, Klocker H, Launoit Y,    Cato A C. Androgen receptor-Ets protein interaction is a novel    mechanism for steroid hormone-mediated down-modulation of matrix    metalloproteinase expression. J Biol Chem. 1996 Sep    27;271(39):23907–13.    A Mammalian Two-Hybrid Assay for the Ligand-Induced Interaction of    N-Terminus and C-Terminus Domains of the Androgen Receptor (Agonist    Mode)

This assay assesses the ability of AR agonists to induce the interactionbetween the N-terminal domain (NTD) and C-terminal domain (CTD) of rhARthat reflects the in vivo virilizing potential mediated by activatedandrogen receptors. (ref. 1). The interaction of NTD and CTD of rhAR isquantified as ligand induced association between a Gal4DBD-rhARCTDfusion protein and a VP16-rhARNTD fusion protein as a mammaliantwo-hybrid assay in CV-1 monkey kidney cells.

The day before transfection, CV-1 cells are trypsinized and counted, andthen plated at 20,000 cells/well in 96 well plates or larger plates(scaled up accordingly) in DMEM+10% FCS. The next morning, CV-1 cellsare cotransfected with pCBB1 (Gal4DBD-rhARLBD fusion construct expressedunder the SV40 early promoter), pCBB2 (VP16-rhAR NTD fusion constructexpressed under the SV40 early promoter) and pFR (Gal4 responsiveluciferase reporter, Promega) using LIPOFECTAMINE PLUS reagent(GIBCO-BRL) following the procedure recommended by the vendor. Briefly,DNA admixture of 0.05 μg pCBB1, 0.05 μg pCBB2 and 0.1 μg of pFR is mixedin 3.4 uL OPTI-MEM (GIBCO-BRL) is mixed with “PLUS Reagent” (1.6 μL,GIBCO-BRL) and incubated at room temperature (RT) for 15 min to form thepre-complexed DNA.

For each well, 0.4 μL LUPOFECTAMINE Reagent (GIBCO-BRL) is diluted into4.6 μL OPTI-MEM in a second tube and mixed to form the dilutedLlPOFECTAMINE Reagent. The pre-complexed DNA (above) and the dilutedLIPOFECTAMINE Reagent (above) are combined, mixed and incubated for 15min at RT. The medium on the cells is replaced with 40 μL/well OPTI-MEM,and 10 μL DNA-lipid complexes are added to each well. The complexes aremixed into the medium gently and incubate at 37° C. at 5% CO₂ for 5h.Following incubation, 200 μL/well D-MEM and 13% charcoal-stripped FCS isadded, followed by incubation at 37° C. at 5% CO₂

After 24 hours, the test compounds are added at the desiredconcentration(s) (1 nM–10 μm. Forty eight hours later, luciferaseactivity is measured using LUC-Screen system (TROPIX) following themanufacture's protocol. The assay is conducted directly in the wells bysequential addition of 50 μL each of assay solution 1 followed by assaysolution 2. After incubation for 40 minutes ar room temperature,luminescence is directly measured with 2–5 second integration.

Activity of test compounds is calculated as the Emax relative to theactivity obtained by 3 nM R1881. Typical tissue selective androgenreceptor modulators of the present invention display weak or no agonistactivity in this assay with less than 50% agonist activity at 10micromolar.

REFERENCE

-   1. He B, Kemppainen J A, Voegel J J, Gronemeyer H, Wilson E M    Activation function In the human androgen receptor ligand binding    domain mediates inter-domain communication with the NH(2)-terminal    domain. J Biol Chem. V274: pp 37219–25, 1999.    A Mammalian Two-Hybrid Assay For Inhibition of Interaction between    N-Terminus and C-Terminus Domains of Androgen Receptor (Antagonist    Mode)

The assay assesses the ability of test compounds to antagonize thestimulatory effects of R1881 on the interaction between NTD and CTD ofrhAR in a mammalian two-hybrid assay in CV-1 cells as described above.

Forty eight hours after transfection, CV-1 cells are treated with testcompounds, typically at 10 μM, 3.3 μM, 1 μM, 0.33 μM, 100 nM, 33 nM, 10nM, 3.3 nM and 1 nM final concentrations. After incubation at a 37° C.at 5% CO₂ for 10–30 minutes, an AR agonist methyltrienolone (R1881) isadded to a final concentration of 0.3 nM and incubated at 37° C.Forty-eight hours later, luciferase activity is measured usingLUC-Screen system (TROPIX) following the protocol recommended by themanufacture. The ability of test compounds to antagonize the action ofR1881 is calculated as the relative luminescence compared to the valuewith 0.3 nM R1881 alone.

SARM compounds of the present invention typically display antagonistactivity in the present assay and have IC₅₀ values less than 1micromolar.

In Vivo Prostate Assay

Male Sprague-Dawley rats aged 9–10 weeks, the earliest age of sexualmaturity, are used in prevention mode. The goal is to measure the degreeto which androgen-like compounds delay the rapid deterioration (˜−85%)of the ventral prostate gland and seminal vesicles that occurs during aseven day period after removal of the testes (orchidectomy [ORX]).

Rats are orchidectomized (ORX). Each rat is weighed, then anesthetizedby isoflurane gas that is maintained to effect. A 1.5 cm anteroposteriorincision is made in the scrotum. The right testicle is exteriorized. Thespermatic artery and vas deferens is ligated with 4.0 silk 0.5 cmproximal to the testicle. The testicle is freed by one cut of a smallsurgical scissors distal to the ligation site. The tissue stump isreturned to the scrotum. The same is repeated for the left testicle.When both stumps are returned to the scrotum, the scrotum and overlyingskin are sutured closed with 4.0 silk. For Sham-ORX, all proceduresexcepting ligation and scissors cutting are completed. The rats fullyrecover consciousness and full mobility within 10–15 minutes.

A dose of test compound is administered subcutaneously or orally to therat immediately after the surgical incision is sutured. Treatmentcontinues for an additional six consecutive days.

Necropsy and Endpoints

The rat is first weighed, then anesthetized in a CO₂ chamber until neardeath. Approximately 5 ml whole blood is obtained by cardiac puncture.The rat is then examined for certain signs of death and completeness ofORX. Next, the ventral portion of the prostate gland is located andblunt dissected free in a highly stylized fashion. The ventral prostateis blotted dry for 3–5 seconds and then weighed (VPW). Finally, theseminal vesicle is located and dissected free. The ventral seminalvesicle is blotted dry for 3–5 seconds and then weighed (SVWT).

Primary data for this assay are the weights of the ventral prostate andseminal vesicle. Secondary data include serum LH (luteinizing hormoneand FSH (follicle stimulating hormone), and possible serum markers ofbone formation and virilization. Data are analyzed by ANOVA plus FisherPLSD post-hoc test to identify intergroup differences. The extent towhich test compounds inhibit ORX-induced loss of VPW and SVWT isassessed.

In Vivo Bone Formation Assay

Female Sprague-Dawley rats aged 7–10 months are used in treatment modeto simulate adult human females. The rats have been ovariectomized (OVX)75–180 days previously, to cause bone loss and simulate estrogendeficient, osteopenic adult human females. Pre-treatment with a low doseof a powerful anti-resorptive, alendronate (0.0028 mpk SC, 2×/wk) isbegun on Day 0. On Day 15, treatment with test compound is started. Testcompound treatment occurs on Days 15–31 with necropsy on Day 32. Thegoal is to measure the extent to which androgen-like compounds increasethe amount of bone formation, shown by increased fluorochrome labeling,at the periosteal surface.

In a typical assay, nine groups of seven rats each are studied.

On Days 19 and 29 (fifth and fifteenth days of treatment), a singlesubcutaneous injection of calcein (8 mg/kg) is given to each rat.

Necropsy and Endpoints

The rat is first weighed, then anesthetized in a CO₂ chamber until neardeath. Approximately 5 mL whole blood is obtained by cardiac puncture.The rat is then examined for certain signs of death and completeness ofOVX. First, the uterus is located, blunt dissected free in a highlystylized fashion, blotted dry for 3–5 seconds and then weighed (UW). Theuterus is placed in 10% neutral-buffered formalin. Next, the right legis disarticulated at the hip. The femur and tibia are separated at theknee, substantially defleshed, and then placed in 70% ethanol.

A 1 cm segment of the central right femur, with the femoralproximal-distal midpoint ats center, is placed in a scintillation vialand dehydrated and defatted in graded alcohols and acetone, thenintroduced to solutions with increasing concentrations of methylmethacrylate. It is embedded in a mixture of 90% methyl methacrylate:10% dibutyl phthalate, that is allowed to polymerize over a 48–72 hrperiod. The bottle is cracked and the plastic block is trimmed into ashape that conveniently fits the vice-like specimen holder of a Leica1600 Saw Microtome, with the long axis of the bone prepared forcross-sectioning. Three cross-sections of 85 μm thickness are preparedand mounted on glass slides. One section from each rat that approximatesthe midpoint of the bone is selected and blind-coded. The periostealsurface of each section is assessed for total periosteal surface, singlefluorochrome label, double fluorochrome label, and interlabel distance.

Primary data for this assay are the percentage of periosteal surfacebearing double label and the mineral apposition rate (interlabeldistance(μm)/10 d), semi-independent markers of bone formation.Secondary data include uterus weight and histologic features. Tertiaryendpoints may include serum markers of bone formation and virilization.Data are analyzed by ANOVA plus Fisher PLSD post-hoc test to identifyintergroup differences. The extent to which test compounds increase boneformation endpoint will be assessed.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adoptions, or modifications, as come within thescope of the following claims and their equivalents.

1. A compound of structural formula I:

wherein: X is selected from —O—, and —N(R⁴)—; R¹ is selected fromhydrogen, C₁₋₃ alkyl, cyclopropyl and trifluoromethyl; R² is selectedfrom: (1) hydrogen, (2) C₁₋₈ alkyl, (3) C₃₋₈ cycloalkyl, (4) C₃₋₈cycloheteroalkyl, (5) C₃₋₈ cycloalkyl-C₁₋₆ alkyl, (6) C₃₋₈cycloheteroalkyl-C₁₋₆ alkyl, (7) aryl, (8) aryl-C₁₋₆ alkyl, (9) amino,(10) amino-C₁₋₆ alkyl, (11) C₁₋₃ acylamino, (12) C₁₋₃ acylamino-C₁₋₆alkyl, (13) (C₁₋₆ alkyl)_(n) amino, (14) C₃₋₆ cycloalkyl-C₀₋₂alkylamino, (15) (C₁₋₆ alkyl)_(n) amino-C₁₋₆ alkyl, (16) C₁₋₆ alkoxy,(17) C₁₋₄ alkoxy-C₁₋₆ alkyl, (18) hydroxycarbonyl, (19)hydroxycarbonyl-C₁₋₆ alkyl, (20) C₁₋₃ alkoxycarbonyl, (21) C₁₋₃alkoxycarbonyl-C₁₋₆ alkyl, (22) hydroxy, (23) hydroxy-C₁₋₆ alkyl, (24)nitro, (25) cyano, (26) trifluoromethyl, (27) trifluoromethoxy, (28)trifluoroethoxy, (29) C₁₋₈ alkyl-S(O)_(p)—, (30) (C₁₋₈alkyl)_(p)aminocarbonyl, (31) C₁₋₈ alkyloxycarbonylamino, (32) (C₁₋₈alkyl)_(n) aminocarbonyloxy, (33) (aryl C₁₋₃ alkyl)_(n) amino, (34)(aryl)_(n) amino, (35) aryl-C₁₋₃ alkylsulfonylamino, and (36) C₁₋₈alkylsulfonylamino; R³ is selected from hydrogen, C₁₋₈ alkyl, andtrifluoromethyl; or R² and R³ together with the carbon atom to whichthey are attached form a carbonyl group, or join to form a 3- to6-membered spiro-carbocyclic ring; and wherein the alkyl groups in R²and R³ are either unsubstituted or substituted with one to three R⁵substituents and wherein any of the aryl, cycloalkyl, orcycloheteroalkyl groups in R² are either unsubstituted or substitutedwith one to three R⁶ substituents; R⁴ is selected from: (1) hydrogen,(2) aryl, (3) aminocarbonyl, (4) C₃₋₈ cycloalkyl, (5) amino C₁₋₆ alkyl,(6) (aryl)_(p)aminocarbonyl, (7) (aryl C₁₋₅ alkyl)_(p)aminocarbonyl, (8)hydroxycarbonyl C₁₋₆ alkyl, (9) C₁₋₈ alkyl, (10) perfluoro C₁₋₈ alkyl,(11) aryl C₁₋₆ alkyl, (12) (C₁₋₆ alkyl)_(p)amino C₂₋₆ alkyl, (13) (arylC₁₋₆ alkyl)_(p)amino C₂₋₆ alkyl, (14) C₁₋₈ alkylsulfonyl, (15) C₁₋₈alkoxycarbonyl, (16) aryloxycarbonyl, (17) aryl C₁₋₈ alkoxycarbonyl,(18) C₁₋₈ alkylcarbonyl, (19) arylcarbonyl, (20) aryl C₁₋₆alkylcarbonyl, (21) (C₁₋₈ alkyl)_(p)aminocarbonyl, (22) aminosulfonyl,(23) C₁₋₈ alkylaminosulfonyl, (24) (aryl)_(p)aminosulfonyl, (25) (arylC₁₋₈ alkyl)_(p)aminosulfonyl, (26) arylsulfonyl, (27) aryl C₁₋₆alkylsulfonyl, (28) C₁₋₆ alkylthiocarbonyl, (29) arylthiocarbonyl, and(30) aryl C₁₋₆ alkylthiocarbonyl, wherein any of the alkyl groups of R⁴are either unsubstituted or substituted with one to three R⁵substituents and wherein any of the aryl, cycloalkyl, orcycloheteroalkyl groups in R⁴ are either unsubtituted or substitutedwith one to three R⁶ substituents; each R⁵ is independently selectedfrom: (1) halogen, (2) C₁₋₈ alkyl, (3) C₃₋₈ cycloalkyl, (4) C₃₋₈cycloheteroalkyl, (5) C₃₋₈ cycloalkyl-C₁₋₆ alkyl, (6) C₃₋₈cycloheteroalkyl-C₁₋₆ alkyl, (7) aryl, (8) aryl-C₁₋₆ alkyl, (9) amino,(10) amino-C₁₋₆ alkyl, (11) C₁₋₃ acylamino, (12) C₁₋₃ acylamino-C₁₋₆alkyl, (13) (C₁₋₆ alkyl)_(n) amino, (14) C₃₋₆ cycloalkyl-C₀₋₂alkylamino, (15) (C₁₋₆ alkyl)_(n) amino-C₁₋₆ alkyl, (16) C₁₋₆ alkoxy,(17) C₁₋₄ alkoxy-C₁₋₆ alkyl, (18) hydroxycarbonyl, (19)hydroxycarbonyl-C₁₋₆ alkyl, (20) C₁₋₃ alkoxycarbonyl, (21) C₁₋₃alkoxycarbonyl-C₁₋₆ alkyl, (22) hydroxy, (23) hydroxy-C₁₋₆ alkyl, (24)nitro, (25) cyano, (26) trifluoromethyl, (27) trifluoromethoxy, (28)trifluoroethoxy, (29) C₁₋₈ alkyl-S(O)_(p)—, (30) (C₁₋₈alkyl)_(p)aminocarbonyl, (31) C₁₋₈ alkyloxycarbonylamino, (32) (C₁₋₈alkyl)_(n) aminocarbonyloxy, (33) (aryl C₁₋₃ alkyl)_(n) amino, (34)(aryl)_(n) amino, (35) aryl-C₁₋₃ alkylsulfonylamino, and (36) C₁₋₈alkylsulfonylamino; each R⁶ is independently selected from: (1) halogen,(2) aryl, (3) C₁₋₈ alkyl, (4) C₃₋₈ cycloalkyl, (5) C₃₋₈cycloheteroalkyl, (6) aryl C₁₋₆alkyl, (7) amino C₀₋₆alkyl, (8) C₁₋₆alkylamino C₀₋₆alkyl, (9) (C₁₋₆ alkyl)₂amino C₀₋₆alkyl, (10) aryl C₀₋₆alkylamino C₀₋₆alkyl, (11) (aryl C₀₋₆ alkyl)₂amino C₀₋₆alkyl, (12) C₁₋₆alkylthio, (13) aryl C₀₋₆alkylthio, (14) C₁₋₆ alkylsulfinyl, (15) arylC₀₋₆alkylsulfinyl, (16) C₁₋₆ alkylsulfonyl, (17) aryl C₀₋₆alkylsulfonyl,(18) C₁₋₆ alkoxy C₀₋₆alkyl, (19) aryl C₀₋₆ alkoxy C₀₋₆alkyl, (20)hydroxycarbonyl C₀₋₆alkyl, (21) C₁₋₆ alkoxycarbonyl C₀₋₆alkyl, (22) arylC₀₋₆ alkoxycarbonyl C₀₋₆alkyl, (23) hydroxycarbonyl C₁₋₆ alkyloxy, (24)hydroxy C₀₋₆alkyl, (25) cyano, (26) nitro, (27) perfluoroC₁₋₄alkyl, (28)perfluoroC₁₋₄alkoxy, (29) oxo, (30) C₁₋₆ alkylcarbonyloxy, (31) arylC₀₋₆alkylcarbonyloxy, (32) alkyl C₁₋₆ carbonylamino, (33) aryl C₀₋₆alkylcarbonylamino, (34) C₁₋₆ alkylsulfonylamino, (35) arylC₀₋₆alkylsulfonylamino, (36) C₁₋₆ alkoxycarbonylamino, (37) aryl C₀₋₆alkoxycarbonylamino, (38) C₁₋₆alkylaminocarbonylamino, (39) arylC₀₋₆alkylaminocarbonylamino, (40) (C₁₋₆alkyl)₂ aminocarbonylamino, (41)(aryl C₀₋₆alkyl)₂ aminocarbonylamino, (42) (C₁₋₆alkyl)₂aminocarbonyloxy, (43) (aryl C₀₋₆alkyl)₂ aminocarbonyloxy, (44)C₀₋₆alkylcarbonyl C₀₋₆alkyl, and (45) aryl C₀₋₆alkylcarbonyl C₀₋₆alkyl;n is selected from 1 and 2; p is selected from 0, 1, and 2; andpharmaceutically acceptable salts thereof.
 2. The compound according toclaim 1, wherein: X is selected from —O—, and —N(R⁴)—; R¹ is selectedfrom hydrogen, C₁₋₃ alkyl, cyclopropyl and trifluoromethyl; R² isselected from: (1) hydrogen, (2) C₁₋₆ alkyl, (3) C₃₋₈ cycloalkyl, (4)C₄₋₆ cycloheteroalkyl, (5) C₃₋₈ cycloalkyl-C₁₋₃ alkyl, (6) C₄₋₆cycloheteroalkyl-C₁₋₃ alkyl, (7) phenyl, (8) phenyl-C₁₋₃ alkyl, (9)amino, (10) amino-C₁₋₃ alkyl, (11) C₁₋₃ acylamino, (12) C₁₋₃acylamino-C₁₋₃ alkyl, (13) (C₁₋₃ alkyl)_(n) amino, (14) C₃₋₆cycloalkyl-C₀₋₂ alkylamino, (15) (C₁₋₃ alkyl)_(n) amino-C₁₋₆ alkyl, (16)C₁₋₆ alkoxy, (17) C₁₋₃ alkoxy-C₁₋₆ alkyl, (18) hydroxycarbonyl, (19)hydroxycarbonyl-C₁₋₆ alkyl, (20) C₁₋₃ alkoxycarbonyl, (21) C₁₋₃alkoxycarbonyl-C₁₋₆ alkyl, (22) hydroxy, (23) hydroxy-C₁₋₆ alkyl, (24)nitro, (25) cyano, (26) trifluoromethyl, (27) trifluoromethoxy, (28)trifluoroethoxy, (29) C₁₋₆ alkyl-S(O)_(p)—, (30) (C₁₋₆ alkyl)_(p)aminocarbonyl, (31) C₁₋₃ alkyloxycarbonylamino, (32) (C₁₋₃ alkyl)_(n)aminocarbonyloxy, (33) (aryl C₁₋₃ alkyl)_(n) amino, (34) (aryl)₁₋₂amino, (35) aryl-C₁₋₃ alkylsulfonylamino, and (36) C₁₋₆alkylsulfonylamino; R³ is selected from hydrogen, C₁₋₈ alkyl, andtrifluoromethyl; or R² and R³ together with the carbon atom to whichthey are attached to form a carbonyl group, or join to form a 3- to6-membered spiro-carbocyclic ring; R⁴ is selected from: (1) hydrogen,(2) aryl, (3) C₁₋₈ alkyl, (4) perfluoro C₁₋₈ alkyl, and (5) aryl C₁₋₆alkyl; wherein any of the alkyl groups of R², R³ and R⁴ are eitherunsubstituted or substituted with one to three R⁵ substituents; andwherein any of the aryl, cycloalkyl, or cycloheteroalkyl groups of R²are either unsubstituted or substituted with one to three R⁶substituents, and wherein any of the aryl, groups of R⁴ are eitherunsubstituted or substituted with one to three R⁶ substituents; n isselected from 1 and 2; p is selected from 0, 1, and 2; andpharmaceutically acceptable salts thereof.
 3. The compound according toclaim 1, wherein: R¹ is selected from hydrogen, methyl, cyclopropyl andtrifluoromethyl; R² is selected from hydrogen, C₁₋₈ alkyl, C₃₋₈cycloalkyl selected from cyclopropyl and cyclohexyl, C₃₋₈cycloheteroalkyl selected from piperidinyl, pyrrolidinyl, azetidinyl,morpholinyl, and piperazinyl, C₃₋₈ cycloalkyl-C₁₋₆ alkyl selected fromcyclopropylmethyl, cyclopropylethyl, cyclopropyl-propyl,cyclohexylmethyl, cyclohexylethyl, and cyclohexylpropyl, C₃₋₈cycloheteroalkyl-C₁₋₆ alkyl selected from piperidinylmethylpyrrolidinylmethyl, azetidinylmethyl, morpholinylmethyl,piperazinylmethyl, piperidinylethyl, pyrrolidinylethyl,morpholinylethyl, piperazinylethyl, piperidinylpropyl,morpholinylpropyl, and piperazinylpropyl, aryl selected from phenyl andbenzyl, aryl-C₁₋₆ alkyl selected from phenylethyl and phenylpropyl,hydroxy, methoxy, trifluoromethyl, trifluoromethyoxy, andtrifluoroethoxy; R³ is selected from hydrogen, methyl andtrifluoromethyl, or R² and R³, together with the carbon atom to whichthey are attached, form a carbonyl group, or join to form a 3- to6-membered spiro-carbocyclic ring; wherein any of the alkyl groups of R²are either unsubstituted or substituted with one to three R⁵substituents; R⁴ is selected from hydrogen, methyl, ethyl, cyclopropyl,trifluoromethyl, and perfluoroethyl; each R⁵ is independently selectedfrom: (1) halogen, (2) C₁₋₈ alkyl, (3) C₃₋₈ cycloalkyl, (4) C₃₋₈cycloheteroalkyl, (5) C₃₋₈ cycloalkyl-C₁₋₆ alkyl, (6) aryl, (7) amino,(8) C₁₋₃ acylamino, (9) (C₁₋₆ alkyl)_(n) amino, (10) C₃₋₆cycloalkyl-C₀₋₂ alkylamino, (11) C₁₋₆ alkoxy, (12) hydroxycarbonyl, (13)hydroxy, (14) cyano, (15) trifluoromethyl, (16) trifluoromethoxy, (17)trifluoroethoxy, (18) (C₁₋₈ alkyl)_(p)aminocarbonyl, (19) C₁₋₈alkyloxycarbonylamino, (20) (C₁₋₈ alkyl)_(n) aminocarbonyloxy, (21)(aryl C₁₋₃ alkyl)n amino, and (22) (aryl)_(n) amino; and wherein any ofthe aryl, cycloalkyl, or cycloheteroalkyl groups in R² are unsubstitutedor substituted with one to three R⁶ substituents, each R⁶ isindependently selected from: (1) halogen, (2) phenyl, (3) C₁₋₃ alkyl,(4) C₄₋₆ cycloheteroalkyl, (5) phenyl C₁₋₃alkyl, (6) amino C₀₋₃alkyl,(7) C₁₋₃ alkylamino C₀₋₃alkyl, (8) (C₁₋₃ alkyl)₂amino C₀₋₃alkyl, (9)phenyl C₀₋₃alkylamino C₀₋₃alkyl, (10) (phenyl C₀₋₃ alkyl)₂aminoC₀₋₃alkyl, (11) C₁₋₃ alkoxy C₀₋₃alkyl, (12) aryl C₀₋₃ alkoxy C₀₋₃alkyl,(13) hydroxycarbonyl C₀₋₃alkyl, (14) C₁₋₃ alkoxycarbonyl C₀₋₃alkyl, (15)phenyl C₀₋₃ alkoxycarbonyl C₀₋₃alkyl, (16) hydroxy C₀₋₃alkyl, (17)cyano, (18) trifluoromethyl, and (19) trifluoromethoxy; n is selectedfrom 1 and 2; p is selected from 0, 1, and 2; and pharmaceuticallyacceptable salts thereof.
 4. The compound according to claim 1, wherein:X is selected from —O— and —NH—; R¹ is selected from hydrogen, methyl,and trifluoromethyl; R² is selected from hydrogen, C₁₋₃ alkyl, benzyl,and cyclopropylmethyl; R³ is selected from hydrogen and methyl; or R²and R³, together with the carbon to which they are attached, join toform a spiro-cyclopropyl ring; and pharmaceutically acceptable saltsthereof.
 5. The compound according to claim 1 selected from:4-(trifluoromethyl)-7,8,9,10-tetrahydrochromeno[7,6-b]azepin-2(6H)-one,4-(trifluoromethyl)-1,6,7,8,9,10-hexahydro-2H-azepino[3,2-g]quinolin-2-one,1,6,7,8,9,10-hexahydro-2H-azepino[3,2-g]quinolin-2-one,8-(R)-methyl-4-(trifluoromethyl)-7,8,9,10-tetrahydrochromeno[7,6-b]azepin-2(6H)-one,8-(S)-methyl-4-(trifluoromethyl)-7,8,9,10-tetrahydrochromeno[7,6-b]azepin-2(6H)-one,8-spirocyclopropyl-4-(trifluoromethyl)-7,8,9,10-tetrahydrochromeno[7,6-b]azepin-2(6H)-one,8-(R,S)-propyl-4-(trifluoromethyl)-7,8,9,10-tetrahydrochromeno[7,6-b]azepin-2(6H)-one,8-(R,S)-dimethyl-4-(trifluoromethyl)-7,8,9,10-tetrahydrochromeno[7,6-b]azepin-2(6H)-one,8-(R,S)-benzyl-4-(trifluoromethyl)-7,8,9,10-tetrahydrochromeno[7,6-b]azepin-2(6H)-one,8-(R,S)-ethyl-4-(trifluoromethyl)-7,8,9,10-tetrahydrochromeno[7,6-b]azepin-2(6H)-one,8-(R,S)-cyclopropylmethyl-4-(trifluoromethyl)-7,8,9,10-tetrahydrochromeno[7,6-]azepin-2(6H)-one,4,8-dimethyl-7,8,9,10-tetrahydrochromeno[7,6-b]azepin-2(6H)-one, and4-methyl-8-(R,S)-propyl-7,8,9,10-tetrahydrochromeno[7,6-b]azepin-2(6H)-one,and pharmaceutically acceptable salts thereof.
 6. The compound accordingto claim 1 selected from:4-(trifluoromethyl)-7,8,9,10-tetrahydrochromeno[7,6-b]azepin-2(6H)-one,4-(trifluoromethyl)-1,6,7,8,9,10-hexahydro-2H-azepino[3,2-g]quinolin-2-one,8-(R)-methyl-4-(trifluoromethyl)-7,8,9,10-tetrahydrochromeno[7,6-b]azepin-2(6H)-one,8-(S)-methyl-4-(trifluoromethyl)-7,8,9,10-tetrahydrochromeno[7,6-b]azepin-2(6H)-one,8-spirocyclopropyl-4-(trifluoromethyl)-7,8,9,10-tetrahydrochromeno[7,6-b]azepin-2(6H)-one,8-(R,S)-ethyl-4-(trifluoromethyl)-7,8,9,10-tetrahydrochromeno[7,6-b]azepin-2(6H)-one,8-(R,S)-cyclopropylmethyl-4-(trifluoromethyl)-7,8,9,10-tetrahydrochromeno[7,6-]azepin-2(6H)-one,and pharmaceutically acceptable salts thereof.
 7. A method of treating acondition which is caused by androgen deficiency or which can beameliorated by androgen administration selected from: osteoporosis,periodontal disease, bone fracture, bone damage following bonereconstructive surgery, sarcopenia, frailty, aging skin, malehypogonadism, female sexual dysfunction, post-menopausal symptoms inwomen, atherosclerosis, hypercholesterolemia, hyperlipidemia, aplasticanemia and other hematopoietic disorders, pancreatic cancer, renalcancer, prostate cancer, arthritis and joint repair, in a patient inneed of such treatment, comprising administering a therapeuticallyeffective amount of a compound according to claim 1 or apharmaceutically acceptable salt thereof.
 8. The method according toclaim 7 wherein the condition is osteoporosis.
 9. A method of treatingosteoporosis in a patient in need of such treatment, comprisingadministering a therapeutically effective amount of a compound accordingto claim 5 or a pharmaceutically acceptable salt thereof.
 10. Acomposition comprising a compound according to claim 1 and apharmaceutically acceptable carrier.
 11. A composition comprising acompound according to claim 5 and a pharmaceutically acceptable carrier.12. The method according to claim 7 wherein the condition is selectedfrom sarcopenia, frailty, and prostate cancer.
 13. The method accordingto claim 12 wherein the condition is selected from sarcopenia, andfrailty.